International Review of Cytology, Volume 88

INTERNATIONAL

REVIEW OF CYTOLOGY VOLUME88

ADVISORY EDITORS DONALD G. MURPHY H. W. BEAMS ROBERT G. E. MURRAY HOWARD A. BERN RICHARD NOVICK GARY G . BORISY ANDREAS OKSCHE PIET BORST MURIEL J. ORD BHARAT B. CHATTOO VLADIMIR R. PANTIC STANLEY COHEN W. J. PEACOCK RENE COUTEAUX DARRYL C. REANNEY MARIE A. DIBERARDINO LIONEL I. REBHUN CHARLES J. FLICKINGER JEAN-PAUL REVEL OLUF GAMBORG JOAN SMITH-SONNEBORN M. NELLY GOLARZ DE BOURNE WILFRED STEIN YUKlO HIRAMOTO HEWSON SWIFT YUKINORI HIROTA K. TANAKA K. KUROSUMI DENNIS L. TAYLOR GIUSEPPE MTLLONIG TADASHI UTAKOJI ARNOLD MITTELMAN AUDREY MUGGLETON-HARRIS ROY WIDDUS ALEXANDER YUDIN

INTERNATIONAL

Review of Cytology EDITED BY

G. H. BOURNE

J. F. DANIELLI

St. George’s University School of Medicine

Danielli Associaies Worcester, Massachusetts

Si.

George’s, Grenada Wesr Indies

ASSISTANT EDITOR K. W. JEON Department of Zoology University of Tennessee Knoxville, Tennessee

VOLUME88

1984

ACADEMIC PRESS, Inc. (Hurcourr Bruce Jovunovich, Publishers)

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84858687

9 8 7 6 5 4 3 2 1

Contents CONTRIBUTORS .............................................................

vii

Lysosomal Functions in Cellular Activation: Propagation of the Actions of Hormones and Other Effectors CLARAM. SZEGOAND RICHARDJ. PIETRAS I. Introduction .........................................................

11. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Compatibility of Lysosomal Properties with Proposed

1

...........

16

Functions in Activated Cells 1v. Selected Cellular Functions Subjected to Lysosomal Influence . . . . . . . . . . . . . . . . V. Integration . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

70 212 243 246

Neuronal Secretory Systems MONACASTEL,HAROLDGAINER,AND H.-DIETERDELLMANN I. 11. 111.

IV. V. VI. VII. VIII. IX. X.

..........

..........................................

ackaging in Peptidergic Neurosecretory Cells. . . . . . . . . . . . . . . Morphological Aspects of the Formation of Peptidergic Neu Axonal Transport in NeurosecretoIy Cells . . . . . . . . . . . . . . . Morphology of Transport and Release-Peptidergic Neurons . . . . . . . . . . . . . . . . . ........... Molecular Organization of Secretary Vesicles in Neurons Biosynthesis and Biochemical Aspects of Packaging and Transport of Neurotransmitters in Nonpeptidergic Neurons Morphological Aspects of Formation of Nonpeptidergic Secretory Vesicles. . . . . . Developmental Aspects of the Hypothalamic-Neurohypophysial System . . . . . . . . Versatility of Neurosecretory Neurons . . , . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . References .

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INDEX . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTENTS OF PREVIOUS VOLUMES AND SUPPLEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . .

V

304 308 318 338 345 366 376 382 40 1 426 438 46 I 465

This Page Intentionally Left Blank

Contributors Numbers in parentheses indicate the pages on which the authors’ contributions begin

MONACASTEL(303), Department of Zoology, Institute of Life Sciences, Hebrew University, Jerusalem, Israel H.-DIETER DELLMANN (303), Department of Veterinary Anatomy, College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011 HAROLDGAINER(303), Laboratory of Neurochemistry and Neuroimmunology, National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20205 RICHARD J . PIETRAS( l ) , Department of Biology, The Molecular Biology Institute, and the Jonsson Cancer Center, University of California, Los Angeles, California 90024 CLARAM. SZEGO( l ) , Department of Biology, The Molecular Biology Institute, and the Jonsson Cancer Center, University of California, Los Angeles, California 90024

vii

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INTERNATIONAL REVIEW OF CYTOLOGY,VOL 88

Lysosomal Functions in Cellular Activation: Propagation of the Actions of Hormones and Other Effectors CLARAM. SZEGOAND RICHARDJ. PIETRAS Department of Biology, the Molecular Biology Institute, and the Jonsson Cancer Center, University of California, Los Angeles, California I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

..................... ............................ A. Mechanisms of Hormone B. The Relevant Properties of Lysoso 111. Compatibility of Lysosomal Properties with Proposed Agonal Mediating Functions in Activated Cells ........................ A. Generalized Scheme. . . . . . . . . . . . B. Circumstantial Evidence of Covert Membranes . . . . . . . . . . . . . . . ............. C. The “Target” Cell: Occurrence and Functional Implications of Specific Recognition Sites for Given Effectors in the Plasmalemma . . . . . . . . . D. Consequences of Ligand IV. Selected Cellular Functions Subjected A. Cell Death and Some Anomalies of Interpretation . . . . . . . . . . . B. Cell Growth and Proliferation.. .......................... C. Cellular Transformation: Indications for a Lysosomal Role . . . . V. Integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. The “Uses” of Compartmentation in the Cellular Econ

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Note Added in Proof .....................

1 1 15

16 16 40 70 70 70

72 73 212 212 220 234 243 243 244 246 246 30 1

I. Introduction A. FIRSTPREMISES

If ever there was a universal indicator of cellular activation (or subduction), it is surface membrane destabilization (or stabilization). All eke follows from this primary event. In an orderly succession of coupled reactions, ever widening to encompass all components and phases of cell function, the remotest reaches of 1 Copyright 19x4 hy Acadcniic P r c s . Inc All rlghis 01 reproduction in any lorm rcrcrvcd ISBN 0.12 7644X8-7

2

CLARA M. SZEGO AND RICHARD J . PIETRAS

subcellular organelles are minutely informed of the change in status quo and are enabled to respond appropriately to the triggering stimulus. Such are the coordinate activities that intimately link nucleus and cytoplasm and their respective suborganellar compartments into a functional whole, and, in turn, promote those quantitatively or qualitatively altered metabolic patterns that may result in greater numbers or differentiated types of cells.

I . The Receptor Concept If one is to trace the progression of these activities from the primary event, it is clear that one must start at the outer cell surface where discriminatory capacity resides. Yet, the cell surface is regularly confronted, even bombarded, with a myriad of potential agonists, endogenous and exogenous. To be on the qui vive toward any and all of these would be disastrous, for, without some means of distinguishing between “valid” and “false” triggers, the efficient economy of eukaryotic cells could not have evolved. Thus, it has been a clarifying and unifying concept that the surface of a given cell is equipped with specialized components able to perform this vital discriminatory function through highaffinity but noncovalent, and, accordingly, reversible, interaction with agonists whose molecular conformation is fundamentally complementary. Nature’s infinite catalog of triggers, present and yet to evolve (or to be designed by man), is immediately brought to a manageable size by the receptor concept, first generalized by Paul Ehrlich (1900; Fig. 1). Mutual recognition has, indeed, proved to be the key to selective responses to specific signals delivered by chemical substances to their “target” cells. Discriminatory capacity of given cells toward closely related molecules is often astonishing, for it appears that receptors and effectors have evolved in coordinate fashion (cf. Niall, 1976, 1982; Blundell and Humbel, 1980; Pierce and Parsons, 1980; LeRoith et ul., 1980; Roth et ul., 1982). Moreover, there are exquisite nuances in the recognition phenomenon that permit distinctions to be drawn among agonists, partial agonists, and antagonists within families of closely related molecular species. This is illustrated from examples representing thyroid and steroid hormones, prostaglandins, and certain opiates (Fig. 2 ) . Additional instances occur among relatively less hydrophobic agents. These latter are too familiar to require specific documentation. 2. Signal verws Noise Granting such specificity, it is necessary, first, to define as precisely as possible the distinctions between specific and nonspecific provocations to the surfaces of responsive cells that represent “signal” and “noise,” respectively. Indeed, and seemingly at paradoxical odds with the specific trigger-receptor interaction defined above, there is a collection of evidence that noise and signal may be “read” by the responding cell as generally equivalent stimuli, not only in degree but in kind. Thus, the coarse provocation delivered, for example, by warming of

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

3

2

FIG. 1 . Diagrammatic representation of the “side-chain’’ theory to illustrate Ehrlich’s concept of specific recognition sites at the cell surface. (1) Complementarity of agonist and receptor. (2) Specific and reversible binding of agonist only to its own receptor. (3) The bound form of the receptor is unavailable for providing negative feedback toward its own biosynthesis. (4) This results in overcorrection by regeneration. (Reprinted by permission, with minor paraphrasing of the text, from the Croonian Lecture, On Immunity with Special Reference to Cell Life, delivered to the Royal Society by Paul Ehrlich, 22 March, 1900; Collected Papers. 1957.)

a cell culture, with or without the further provision of fresh serum and other nutrients in profusion, or even relative anoxia, may have consequences similar in whole or in part to those elicited by the pinpoint signal delivered by a true agonist-even to promoting induction of specific proteins and, perhaps, mito-

AGONISTS AND PARTIAL AGONISTS A. ESTROGENS

& &

HO

Estradiol-17p (active)

...OH

HO

Estradiol-17u (essentially inactive)

HO

C2H5

Estriol (relatively inactive)

Tamoxifen (some agonal effects1

B. ANDROGENS P

CH3 I

~ : '@ H

/

0 Testosterone-17/9 (act we)

0 Testosterone-17a (inactive)

5-Di hydrotestosterone (DHT; intensely active)

/

CI

0

II C-N,

o&

A H 5

C2H5

[A CH3

C ypraterone 178- Jb -diet hy Ic a r ba (antiandrogen with moyl-4-methyl-4-oza-5asome progestational androstan-3-one effects) (inhibits conversion of testosterone - 1 7 p to DHT; has moderate affinity for androgen receptor 1

B,

C. ADRENOCORTICOIDS CHZOH

CHZOH

I

I

0 I! -0eoxycorticosterone

Aldosterone (minerolocorticoids)

VI

D.

0d

0 Cortisol (glucocor ticoid)

=

O

A spirolactone (minerolocorticoid antagonist)

PROGESTATIONAL STEROIDS

OH

Progesterone (active)

Norethinodrel (contraceptive)

Pregnan-3a,20a-diol (inoct ivel (continued) FIG. 2A-D.

See legend on p. 9

AGONISTS AND PARTIAL AGONISTS

ANTAG ONISTS (svnthet ida

E. GIBBERELLINS

Gibberellin A3 (active)

m

Gibberellin A,2

Gibberellin As

(less active; precursor)

(inactive; degradation product 1

F. INVERTEBRATE HORMONES

Hop

OH OH

HO

I OH

HO

0 20-hydroxy Ecdysone (active)

I OH

HO

0

(p')

Ecdysone

('d)

(relatively inactive)

Fluorogibberellin A,2

H3c0m

H,CO

0 ‘H Juvenile Hormone I

Juvenile Hormone II

Juvenile Hormone

m

(active, naturally o c c u r r i n g )

/

o

0

u

“

0

Precocene 2 (natural product from Ageratum houstonianum; induces toxic effect typical of JH excess)

4

0

Synthetic analogs (with greatly enhanced JH -activities)

G. PROSTAGLANDINS O 0 -H

HO

“

‘&OOH

‘0H

HO

OH

PGE, PGFZ, (active; frequently counterpoised)

k

O

H

OH

HO

PGFzp (inactive) (continued) FIG. 2E-G.

See legend on p. 9.

eoo 9,11-Deoxy-7-oxa-prostanoic

acid

AGONISTS AND PARTIAL AGONISTS

ANTAGONISTS (synthetic)'

ti. PROSTACYCLINS

o=rcOO

JTcooH L

9

OH

OH

Prostocyclin PGI, (active)

OH

OH

6-Ketoprostacyclin (inactive)

t

Func t io no I ant o g on ist s

I . THROMBOXANES 0" -"-COOH OH Thromboxone A, (active)

'

*'-COOH OH

Thrombaxane 6, (inactive)

J. THYROID HORMONES I

I

ty2

I

I

I

I

HO ~ O ~ C H - C H , - - C O O H

O H C 0C H --C H 2Q -O -Q -H O -

1

L-3,5,3: 5'-Tetraiodothyronine; throxine;

T4

3.3'-Diiodothyropropionic acid

(ac t ivel N"2

H O b O & C H 2 - C H - C O O lI

I L-3,5,3'-Triiodothyronine; (more active)

T3

L-3,3@,5'-Triiodothyronine (reverse T3 (rT3); naturolly occurring; virtually inactive)

3' Isopropyl,-3,5 dibromothyronine (synthetic analog; more active than T), ~~~

~~

aUnless otherwise noted FIG. 2. Representative examples of agonists, partial agonists, and antagonists: relatively hydrophobic structures

10

CLARA M. SZEGO A N D RICHARD J . PIETRAS

genesis. Some selected examples of this well-known, but rarely integrated, set of observations are presented in Table I and elsewhere in the text. Inspection of Table I reveals that a wide array of “nonspecific” but by no means invariably noxious stimuli may lead in given cells to metabolic and morphologic events generally construed as anabolic and/or developmental. Likewise, it has long becn recognized that serum itself, added in vitrn to surviving cells or tissue explants, especially at times when the former have reached their growth plateau, whether or not confluency has also been achieved, possesses growth-supportive, if not -stirnulatory potential (cf. Eagle, 1965; Temin, 1971; Baker and Humphrey, I97 I ; Holley, 1975). Generally, the latter observations have been construed to mean that the activity of serum reflects its content of specific growth-promoting substances, whether polypeptide or of relatively low molecular weight (cf. Hayashi and Sato, 1976; Gospodarowicz and Moran, 1976), that, in many instances, can be correlated with the presence of certain hormones. In turn, the latter may, in judiciously chosen concentration for the given cell type, substitute altogether for the putative serum components (Bottenstein et al., 1979). On the otlicr hand, there are many investigators who view the contribution of serum and its derivatives as serving generalized nutrient, and thus relatively nonspecific, functions (cf. Rubin, 1975; Balk et al., 1981),especially since the raw serum may, often with impunity, be heat or acid treated (e.g., Fujiwara et al., 1980). Indeed, in at least one contact-inhibited cell line, simple alkalinization promoted the same quality and degree of biochemical responsiveness that was achieved with serum (Ceccarini and Eagle, 1971). Regardless of this sharp divergence in interpretation, it is instructive to note the parallels between the functions of serum in supporting proliferative activity and those of nonspecific stimuli (cf. Table I), for example, when criteria of amino acid incorporation into protein, or that of thymidine into DNA, are applied. But an additional parallel exists. Whether the resultant growth or differentiation is attributable to serum or to some form of nonspecific, not necessarily noxious, stimulus, the response has a further concomitant: induction of lysosoma1 enzymes and/or the organelles themselves (Rose, 1957; Cohn and Benson, 1965; Ahearn et al., 1966; Cohn and Fedorko, 1969; Gordon and Cohn, 1973; Reikvam et a l . , 1975; Wang and Touster, 1976). Such induction, in turn, may be referable to the initial surface phenomenon, upon which attention was focused above. Especially significant in this context is recent work which has demonstrated that intraperitoneal injection of isologous serum leads within 2 minutes to a 3-fold, and by 30 minutes, to a 7-fold increase in microvillar formation and surface microvesiculation of mesothelial cells of mouse omentum (Madison et al., 1979). Similar, but more gradual effects are elicited by as well characterized a protein as bovine serum albumin. Moreover, in quiescent neuroblastorna cells, the surface-perturbing effects of serum can be identified as a virtually immediate depolarization associated with a sharp decline in membrane resistance (Mool-

TABLE I BIOCHEMICAL A N D MORPHOLOGIC CONSEQUENCES OF SELECTED NONSPECIFIC STIMULI: THEBACKGROUND “NOISE” Stimulus

Consequence

Interpretation

Uterus in siru of ovariectomized rats

Estrogenicomimetic effects on acute blood flow, water imbibition at 4 hours

Ligature

Oviduct of diethylstilbestrolprimed chicks

Induction of avidin, highest in immediate region of ligature

Irritation by trauma or stretch, of locally instilled saline serves to attenuate the net influence of estrogen-released biogenic amines on biochemical and mitogenic evidences of uterine stimulation Membrane damage or histamine liberation believed excluded on basis of very limited attempts at blockade by cortisol, CaCI2, or promethazine ip (see, however, Szego, 1972b)

Stretch (10.8%, 18 hours)

Embryonic chicken skeletal myotubules in vitro

Without increase in cell volume, increased accumulation of [3H]AIB, [I4C]amino acids; increased incorporation of latter into general cellular proteins and myosin heavy chains; increased net protein and myosin heavy chains; increased DNA

A. Mechanical lntraluminally applied 0.154 M NaCI

Object

Reference

Szego and Sloan (1961)

Heinonen and Tuohimaa (1976, 1979)

Vandenburgh and Kaufman (1979)

(conrinued)

TABLE I (Continued) Stimulus Stretch (intermittent)

Endocytosis of I-pm latex beads

Object Rat diaphragm incubated in vitro

B-16 mouse melanoma adapted to in vitro cultivation

Consequence

Interpretation

Reference Reeds er al. (1980)

>2-fold increase in “synthesis” of noncollagen protein; increased glucose uptake and lactate output Augmented secretion of neutral proteinase and collagenase

Some indication that in-

Enhancement of axon fonnation (morphologic differentiation); increased cell and nuclear size (morphologic maturation); >lo-fold increase in acetylcholinesterase activity Translocation of unoccupied estrogen receptor to the nuclear fraction Reversible, ligand-independent redistribution of surface receptors for Ig, H2, and Thy-1.2 antigens, some for Con A

Some evidence of participation of microtubules in induction of differentiation, as judged by inhibitory effect of vinblastine

Prasad (1971); Prasad and Vemadakis (1972)

Mechanism undetermined

Cannon and Gorski (1976)

Association of microvilli with cap region suggested activation of underlying mechanoeffector systems

Yahara and Kakimoto-

creased mobilization of energetic resources may be involved Correlation of surface perturbation with “expression of [enzyme] potential.” Best indication in cell line “low in . . . basal proteinase activities”

Sauk and Witkop (1978)

e

N

B. Radiation and chemioeledric X-Irradiation

Mouse neuroblastoma cells in vitro

Hypertonic sucrose

Immature rat uteri in v i m

Hypertonic buffer

Murine lymphocytes and thymocytes

Sameshima (1977)

X-Irradiation (20,000 rad)

Contact-inhibited human glial cells

Electrical excitation; potassium depolarization

Squid giant axon

Diethyl ether; chloroform

Larvae of Trichosia pubescens

Methylene blue

Mouse peritoneal macrophages cultured in Medium 199 Rat liver microsomes

DMSO

~~

~

By 6 hours, augmented microvillar and endocytotic activity; conspicuous alterations in lysosomal structure, and somewhat later, in number; proliferation of Golgi Protein release to external medium

A large and several smaller puffs in the polytene chromosomes of the salivary glands within a few minutes after exposure; maximal at 60-100 minutes; intense incorporation of [3H]uridine (autoradiography), and accumulation of nonhistone proteins (acidic fast-green stain) in the puff region Induction of plasminogen activator secretion Phosphorylation of tyrosyl residues in a 170K protein corresponding to EGF receptor

Origin of autophagic vacuoles from preexisting lysosomes and/or “flattened vacuolar cytoplasmic elements”

Hamberg et al. (1977)

Solubilization of a particular group of proteins in close association with the membrane Increase in gene transcription at puff; potential ef.fect of lipid solvents on permeability of plasma membrane to inducing substances of unspecified nature that are, in turn, translocated to nucleusa

Pant el al. (1978)

“Electrical stimulation of the hexosemonophosphate pathway” Parallels to EGF actions in this and other respects noted

Schnyder and Baggiolini (1980)

Amabis and Janczur (1978); cf. also Wigglesworth (1957); Kroeger (1967)

Rubin and Earp (1983)

~

(continued)

TABLE I (Continues) Stimulus

Object

C. Relative anoxia; prolonged - incubation at 37°C Left ama Coronary artery occlusion

Prolonged (&hour) incubation at 37°C

Immature rat uteri

Incubation for 0.5 to 2 hours

Epithelium of infantile mouse

Several days of primary culture

Rat hepatocytes and hepatoma cells

Consequence

Interpretation

Increased numbers of [3H]thymidine-labeled nuclei and mitoses in left arrial muscle cells at 3-40 days after left ~ e n tricular infarction

“Reactive synthesis” following edema and exaggerated sarcoplasmic and nuclear basophilia. possibly secondary to “mitral [and associated biochemical] insufficiency” Incubation conditions mimic estrogen action and are “dependent upon protein synthesis“ and a permissive temperature

Rurnyantsev and Mirakjan (19681

Relative anoxia; estrogen uptake unaffected

Ljungkvist and Terenius ( 1970)

Profound changes in cytoskeletal composition during cell culture

Franke er 01. (1981a)

Progressive increase in RNA polymerase (RNA-P) activity; enhanced incorporation of [‘4C]glycine into protein. Both effects similar to those of specific estrogen stimulation; effects on RNA-P suppressed at 23°C or by cycloheximide treatmenth In absence of estrogen, mild to advanced autolyiic changes seen by TEM, but undetectable by light microscopy General induction of vimentin filaments and maintenance of production of cytokeratins

Reference

Nicolette et af. (1968); Nicolette (1 969)

“ S e e also comments by Berendes (1972) and Sin (1975) in context of “heat shock” puffs in salivary glands of Drosophih larvae. In the latter case, the puffs were induced by extracts of “mitochondria” prepared after heat shock exposure However. such preparations have long been recognized for their contamination with lysosomes (cf. Vignais and Nachbaur, 1968). bSee Table XXllI and effects of antibiotics on lysosomal structure and function (textl.

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

15

enaar et a l . , 1979). These phenomena, suggestive of a transient increase in Na+ conductance, were attributed to putative growth-promoting factors in serum because of the minimal electrophysiological response to the addition of depleted media. Thus, surface membrane events associated with the application of serum and/or given proteins appear primary, and clearly precede the biochemical and morphologic consequences. Indeed, as will be documented below, it appears possible to trace a chain of interlocking events which leads in due course to the latter outcome. Accordingly, this background noise, which can, under some circumstances, overwhelm signal, must be kept in mind throughout our attempts to analyze the potential role of lysosomes, through limited recompartmentation of their specialized components, in the amplification and propagation of the initial effects of the primary trigger that destablizes, and thus activates, given cells.

B. OBJECTIVES AND SCOPE On the basis of these considerations, we shall restrict our analysis of the mechanisms by which the activities of endogenous signals in the form of hormones and certain neurotransmitters are intercepted from the extracellular environment, transduced, progressively propagated, and interpreted in the language of that cell capable of perceiving their presence: i.e., having a given number of recognition sites with the appropriate topology on its surface available at the moment, together with a means of coupling the amplified information derived from the ligand-receptor complex to more remote cellular events. On occasion, we shall consider similar circumstances in relation to exogenous effectors, such as drugs, selected carcinogens, and certain regulatory substances that do not fall into the category of hormones. Some instructive parallels appear to emerge from such comparisons, as will be documented below. On the basis of a growing body of evidence, we have proposed that events set in motion by interaction of surface membrane of target cell with specific ligand are associated with regional endocytosis and site-specific modification of lysosoma1 structure and function and are intimately related to the molecular means by which coordinated cell growth and differentiation are achieved in response to tropic hormones (Szego, 1971a,b, 1974, 1975, 1978; Szego et a l . , 1971; Szego and Pietras, 1981). Taking into account the combined properties of lysosomes on the one hand, and the characteristic pleiotropic actions of hormones on the other hand, it has been suggested that primary lysosomes function in selective uptake of the agonist and, in their secondary, covertly labilized form, in its transcytopiasmic migration and in its introduction into the nucleus of the hormoneactivated cell, accompanied by “transformed” and/or diminished receptor and very limited amounts ( ‘‘microquanta’’) of lysosomal constituents. It will be one purpose of the present account to evaluate aspects of this

16

CLARA M. SZEGO AND RICHARD J. PIETRAS

proposal in light of numerous more recent findings. We hope to identify, as far as possible, the individual steps in the staging of such a vectorial pathway and to assess’their potential metabolic consequences in the processing and execution of information delivered by agonist. A further aim of this essay is to determine, from analysis of as wide an array of effectors and target cells as possible, whether such a pattern is generalized or unique to only certain classes of effectors or target cells. Finally, from these and independent data, implications of lysosoma1 function in propagation and coordination of transcellular events will be considered. It is, of course, recognized that in presenting an apparently sequential array of metabolic events one must guard against the bias inherent in the various sensitivities of the several analytical methods themselves. Of even greater concern is the danger of confusing concornirancy with causality, a pitfall that we hope to avoid. Taking these risks advisedly, we hope that identification of serious gaps in understanding, leading, potentially, to stimulation of more definitive work, will compensate for the inevitable prematurity of an integrative effort applied to currently unfolding data. It is hoped that integration of information to be derived from analysis of these interlocking problems will contribute to our growing, but still very incomplete, understanding of the critical molecular events associated with triggering of cellular responses to tropic hormones and other effectors.

11. Perspective

Having put the cart before the horse in presenting some of the complexities of the subject that have prevented facile integration of the many, apparently unrelated, observations into a coherent whole (cf. Szego, 1982), we now address directly the problems in accounting for hormone action that have necessitated the fresh outlook and the change in emphasis that led to the present hypothesis. A. MECHANISMS OF HORMONE ACTION 1. Evolution of Ideas What Is Limiting.? As with any other developmental phase of functional biochemistry, ideas on the primary events in hormone action have generally reflected the prevailing concepts of the time. Attempts to understand hormoneldrug action in physical terms were at first rather sporadic. Efforts of early cell physiologists centered upon modulation of the cell surface and its role in controlling exchanges with the extracellular environment (cf. Meyer, 1899; Overton, 1901; Traube, 1904; Ponder, 1933). This semiquantitative outlook was soon eclipsed by the more stringent formulations of the enzymologists, who, influenced in part by the “p-hypothesis” of Crozier (1926), which formally

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

17

advanced the proposal that the slowest of an integrated series of presumed enzymic reactions was the overall pacemaker, emphasized potential inhibitory functions of agonists upon the activities of prevailing enzymes to the exclusion of “positive” controls. The latter represented the “unthinkable” in the tight logic of the times (cf. Green, 1941). In wake of the exponential advance of Lipmann (1941) on energy-yielding mechanisms, this limiting view was to give way to the concept of hormonal participation in metabolic reactions as coenzyme, subject to reversible oxidationireduction (cf. Villee and Hagerman, 1953; Ball and Cooper, 1957; Langer and Engel, 1958; Talalay and Williams-Ashman, 1958; and McKerns and Bell, 1960). When, in turn, this phase yielded to the electrifying concept of the operon (Jacob and Monod, 1961), the latter was, virtually immediately, transposed into the hormonal mode: “the” limiting factor was the means of delivering fresh instructions to protein-synthesizing machinery, i.e., transcription of template and/or other forms of RNA (Karlson, 1963; Edelman et af., 1963; Wilson, 1963; Talwar and Segal, 1963; Noteboom and Gorski, 1963; and Ui and Mueller, 1963). When, some time later, it became evident that neither of the latter two views, themselves not mutually exclusive, was wholly adequate to explain all facets of hormone action, and, indeed, when evidence began to accumulate that indicated far greater complexities than had previously been envisioned,’ it became clear that much deeper analysis was required. Somewhere in the course of these developments, there arose the generalization that the steroid and peptide hormones functioned by independent and mutually exclusive mechanisms (Table 11; see Szego, 1978, for review). This dichotomous view, which no longer appears tenable (Szego, 1974, 1975, 1976, 1978; Szego and Pietras, 1981), was, in fact, based upon inadequate premises: that steroid hormones, being fat-soluble, were not appreciably hindered by the lipid bilayer of the plasmalemma. Instead, they readily and indiscriminately entered all cells but were retained, on encountering “cytoplasmic” receptor, exclusively within “target” cells, thereupon to be transferred, by an unknown mechanism, into the nucleus. In contrast, the peptide hormones, because they were thought to be restrained from crossing the plasmalemma by mass and charge, required participation of secondary messenger(s) for propagation of the effects of their initial recognition at the cell surface. As part and parcel of such divergence in mode of operation of steroid and peptide agonists, it was widely and confidently believed (despite cogent evidence to the contrary), that the action of steroid hormones at their cellular targets was, unlike that of their peptidal counterparts, unaccompanied by abrupt alterations in cyclic nucleotide and/or ionic gradients or other indications of membrane perturbation. ‘In part, this impasse was due to the unrestrained enthusiasm with which data obtained in prokaryotes were applied to eukaryotic organisms, often with the added complications arising from the effects of the highly toxic antibiotics used as “specific” inhibitors of protein and RNA synthesis (see Section IV,A).

18

CLARA M. SZEGO AND RICHARD J . PIETRAS

TABLE 11 POSTULAltU DICHOTOMY IN

M o D t b 01.ACTION . OF STEROID AND PtPTlDF

Parameter

Peptidesb

Location of receptor Ccllular entry

Outer plasmalcnima

Nucleotide cyclase activation Nuclear actions

Yes Indirect

No'

HORMON~S 2 hours

Lymphocytes coincubated 1 hour with labeled macrophages Primary chick myoblast cultures

Autoradiography (TEM)

Jonas et al. (1976)

Kinetics of incorporation of exogenous mRNA into polysomes; faithful translation of is0 and heterologous poly(A) -mRNA

Mroczkowski et al. (1980)

Transfer small, except from antigen-stimulated macrophages Unambiguous study of translational controls during development sheds incidental light on entry of exogenously supplied mRNA into cultured cells and its tissue-specificr translation; cf. also Segal et al. (1965)

ICC (LM)

Nolin and Witorsch (1976)

+

Alveolar cells of lactating rat mammary glands‘

Specific staining of apical regions of epithelial cells (remote from blood supply), strongly indicating prior entry of endogenous hormone (continued)

Ligand [marker]

Target cell(s)

Criteria

Reference

[HRPI-rabbit Ab->

Rat sex accessory organs

ICC (LM)

Witorsch and Smith (1977): Witorsch ( I 978)

[ ll'I]oPRL

Rat liver

Biochemical: cell fractionation

losefsberg er a!. (1979)'

Rabbit adipocytes

Uptake (K l o l l M - I ) and binding studies of isolated cells and components

Par1 er al. (1977)'

[Rho]-

Cultured 3T3-4 murine fibroblasts

Video-intensified fluorescence microcopy

Cheng et a/. (1980);cf. also Maxfield er al. (1981a)

['"'IIT,

Rat liver parenchymal cells and their PM vesicles

Rapid centrifugation technique

Rao et a!. (1981)''

Comment Androgen dependency of immunospecific staining. conspicuously at Golgi in ventral prostate and seminal vesicle; staining seen throughout cytoplasm in epididymis and vas deferens; spermatozoa negative Labeled hormone (retaining full rebinding-integrity to fresh membrane preparations) strongly concentrated in Golgi fractions

Uptake of T3,T4 by lipid components 2-5 X that of intact cells, indicating passive diffusion unlikely Surface association, clustering, and vesicular entry of these low MW, relatively hydrophobic hormones paralleled observations by same group on a*M, insulin Evidence for accumulation of hormone against a gradient

Toxins (bacterial) [HRPI-cholera

W

Cultured murine new roblastoma cells

TEM

Joseph et al. (1978. 1979)

Diphtheria

Chinese hamster lung (V79): African green monkey: kidney (VERO) cells

Draper and Simon (1980); Sandvig and Olsnes (1982)

[Rho]-

Murine 3T3 and human W138 fibroblasts in culture

Biochemical: influence of lysosomotropic drugs on metabolic pathways deranged by the toxin As for insulin. above (Schlessinger et al., 1978)

[1251]-, [FITCI-Ab-Tetanus

Cultured rat cerebral brain cells

Biochemical: influence of unlabeled ligand, tetanus antitoxin, and gangliosides on kinetics of cell association of the toxin

Yavin et al. (1981)

Epithelial cells of opened follicles rat and pig thyroid

TEM

Herzog and Miller (1979)

TSH [Cationized Ferl-latex spheres

Keen et al. (1982)

Binding and internalization; predominant association with GERL Evidence for a lysosome-mediated step in the toxicity of endocytosed toxin Vesicular endocytosis similar in both sensitive (human) and insensitive (murine) cells Confirms gangliosidal nature of receptor(s) and speculates on their role as “shuttle” vehicles

TSH-stimulated vesicular endocytosis, preferentially at coated pits, accompanied by lysosomal uptake by 15 minutes; some also at Golgi (continued)

TABLE 111 (Continued) Ligand [marker] Virus Sindbis; vesicular stomatitis

Target cell(s)

Criteria

Reference

Chick cells; MDBK cells

Lack of sensitization of host cells to lysis by Ab + complement

Fan and Sefton (1978)

BHK-21 cells

Biochemical: suppression of productive infection by lysosomotropic arnines ICC at TEM level

Talbot and Vance (1980)

Herpes simplex

Rabbit corneal cells

S e d i k i Forest (SFV) [Rho]-, IFITCI-,

BHK-21 cells

Fluorescence microscopy; E M ; biochemical: infectivity dependent upon low PH

Helenius et 01. (1980a,bp

MDCK cells

Biochemical and morphologic (ICC)

Matlin et al. (1981)

Hansen et al. (1979)

W

N

[35S]-

Fowl plague 13-%]-; also [Fer-20 Ab]-

Comment Adsorptive endocytosis implicated (cf. Dales, 1973; Tardieu et al., 1982) by apparent lack of membrane-fusion mediated entry (as in the case of Sendai ViNS) Data support a lysosomal route of cytoplasmic entry and infectivity Findings, comprising timecourse of subcellular distribution of viral antigen, including into nucleus, support biochemical observations (see refs.) Adsorptive endocytosis into coated pits and vesicles, followed by fusion with (lysosomal) vesicles at low pH As above

also Szego (1974, 1975); Table IV in Szego (1978); as well as Neville and Chang (1978); Petrusz (1978); Gorden eral. (1980a); Goldfine (1981a.b); Pastan and Willingham (1981); King and Cuatrecasas (1981); and Middlebrwk and Kohn (1981). Although persuasive collectively, the data shown in this summary (as well as in a number of additional tables and figures to follow) possess certain inherent limitations. (1) Liberation of isotopic label from agonist so marked may occur with variable degrees of efficiency on exposure to cellular components at surface or intracellularly. (2) Products of limited or more extensive proteoiysis may

or may not retain activity intrinsic to the native material. (3) Confidence in localization of marker at the EM level requires careful statistical analysis, ideally on observations in serial sections. (4)Immunocytochemical criteria, even with rigorous controls, could be recognizing an unspecified fragment of the native material. (5) Resolution of some of the cited procedures is not yet well advanced. (6) Cellular architecture is occasionally inadequately preserved, through faulty fixation (cf. Novikoff, 1980), a problem that gives rise to inappropriate conclusions on significance of subcellular-marker localization. (7) Finally, the relative contributions of nonspecific vs. specific interactions leading to internalization of bound ligand are only rarely assessed, especially as these are further superimposed on the background “noise” (see Table I). bFITC, Fluorescein isotbiocyanate; Hypox, hypophysectomized; SEM, scanning electron microscopy; TEM, transmission electron microscopy; LM, light microscopy; HRP, horseradish peroxidase; PM, plasmalemma; hCG, human chorionic gonadotropin; ICC, immunocytochemistry; H , hormone; R, receptor; LH, luteinizing hormone; MSH, melanocyte stimulating hormone; MVB, multivesicular body; Ab, antibody; Ag, antigen; AcPase, acid phosphatase; PHA, phytohemagglutinin; drg, dorsal root ganglion; scg, superior cervical ganglion; Con A, concanavalin A; WGA, wheat germ agglutinin; WFA, Wistariafloribunda agglutinin; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; LHRH, luteinizing hormone-releasing hormone; bPTH (1-34), bovine parathyroid hormone, active segment comprising residues 1-34;GERL, Golgi-endoplasmic reticulum-lysosomal system; FPR, fluorescence photobleaching and recovery; 0, ovine; T,, 3,5,3’-triiodo-~-thyronine; T,. 3,5.3’,5’-tetraiodo-~-thyronine (thyroxin): MDBK cells, Maden-Darby bovine kidney cells; Fer, fernitin; Rho, rhodamine ?Preparations of anti-hCG used were known to cross-react with rat gonadotropins. mainly LH. dSheep. eThis early paper on peptide hormone internalization, using sophisticated ultrastructurallautoradiographiccriteria, was generally discounted because of the presumptive disposal/degradation implications (cf. Table I1 in Szego, 1978). muman. RAb directed against surface membrane glycoproteins hSee Table VIII. However, problems related to vesicular internalization of free rhodamine (cf. Drucker et al., 1982) may render these and similar observations less than unequivocal. ‘See Fig. 6. /Human. LData presented to demonstrate recognition and internalization of free Fer at coated-PM region [cf. Fawcett (1965); Lagunoff and Curran (1972)] occurred at loci independent of presumptive receptors for [Ferl-LDL. ‘Human and murine sources. ‘“Human and rat sources “No attempt is made here to integrate the exponentially growing information on incorporation of foreign DNA into the genome of the recipient.

(continued)

TABLE I11 (Continued) -

"The far-sighted papers and review of Ledoux (see 1965) recognized the likelihood of intracellular introduction of these highly charged macromolecules by processes such as "pinocytosis." However, specific recognition sites were not envisioned, nor have such been identified, as yet. This family of macromolecules is here included primarily for heuristic reasons (cf. Szego, 3975). Comprehensive reviews of the cellular uptake and fate of polynucleotides are now available (e.g., Stebbing 1979). pFrom lactating mammary glands of isogenic rats or from Micrococcus Iysosodeikticus YPresent in autologous macrophages of mice. rPoly(A) mRNA also taken up but not associated with polysomes and thus: untmnslated; mRNA for brain- and liver-type creatine kinase not utilized in translation. .'Directed toward endogenous PRL: special procedures required to eliminate primary antibody-independent direct binding of the rabbit y-globulin to the target cells. 'See N o h (198Ob) for additional cellular targets in the postpartum rat. lSee also Fig. 12. "lodination of ligand performed by the direct chloramine-T method. Recent work has demonstrated that, except when carried out in the presence of substances capable of attenuating the strongly oxidizing effects of the latter, the above procedure results in production of an iodinated peptidal ligand whose association with receptor is irreversible, possibly covalent (Comens ef al., 1982). Iodination with the aid of lactoperoxidase did not lead to similar artifact (Comens et al.. 1982). See also, C . Heinrich (1982). wBoth chlorarnine-T and lactoperoxidase procedures utilized for catalyzing iodination. Since both products were apparently used interchangeably, it was not possible to determine from this repon which product yielded the given results. Wsed modified chloramine-T method of Frazier er al. (1974) with rigorous care in evaluating retention of native character of the peptidal ligand. ~

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

35

(Szego, 1975; see also Table V). Can such generality (which may, on the basis of limited data already available, extend also to aspects of the actions of certain viruses, carcinogens, and toxins; see below) be a mere evolutionary accident? That does not seem likely. Instead it appears that recognition of ligand associated with plasmalemmal perturbation (or stabilization, in the case of a limited number of agonists such as insulin, prolactin, and antiinflammatory steriods at optimal concentrations), is common to the acute functions of agonists with extremely variegated structures. In turn, this evidence of the exquisite discriminatory capacity of the target cell for selectivity in relating to the potential agonists in its environment is surely attributable to the receptor population available at its dynamic surface at the moment.* In contrast to the extreme specificity of the surface recognition phenomenon, the subsequent pleiotropic effects of the several agonists appear to be more broadly programmed, and thus shared by diverse cell types in qualitatively similar fashion.

3. Unresolved Problems Through our two-decade preoccupation with transcriptional controls exerted by regulatory agents upon their respective target cells, we have, with notable exceptions, neglected to analyze in adequate depth concomitant, and even precedent, activities in the cytoplasm. Moreover, given the extraordinary coordination between nuclear and cytoplasmic responses attributable to the primary perturbation of agonal capture, we have generally failed to seek in systematic fashion, much less to identify, the precise coupling mechanisms by which such manifestly two-way communication is achieved. Above all, we have neglected detailed analysis of the cytostructural correlates of the subcellular compartmentation, which yields the economical, poised system capable of serving as a means of rapid propagation of initial triggering event, as previously sequestered, potential reactants are rendered accessible to various degrees. By the same token, such accessibility may result in metabolic activities that may mask or overwhelm other functions-a source of profound errors of interpretation not yet widely recognized, especially in relation to labeling of metabolic products from isotopic precursors that has been equated, often without adequate foundation, with net “synthesis. ’ ’ 4. Requirements of Any Hypothesis Purporting to Account for Totality of EfSector Action In reviewing the formidable volume of literature that is presented merely in token exemplary form in Figs. 1-3 and Tables 11, IV, and V, above, it is evident *The coexistence, side by side, of cells responsive, as well as unresponsive, to steroid (Szego et a ! . , 1977; Kierszenbaum et a l., 1980; Nazareno er al., 1981) or peptide (Varga er al., 1974) hormones, is a phenomenon that appears attributable, in part, to the turnover of cell surface constituents including macromolecules with recognition properties for the given agonist.

TABLE IV TIMECOURSEOF RESP~NSESOF THYROID GLANDTO TSHQ Time

< 10 seconds < 30 seconds W QI

3-6 minutes 5-15 minutes

Effect TSH,,binding to plasma membrane Enhinced accumulation of CAMP CAMP peak Intense apical surface activity Formation of large bulbous pseudopods which engulf luminal colloid Masses of colloid droplets rapidly filling apices of follicular cells Phagocytosis of colloid in parallel with lysosome redistribution, basal to apical Exocytosis of proteins into follicle lumen immediately on pseudopod formation Enhancement of glucose Q ~ , ac: tivation of the pentose phosphate pathway Depletion of serotonin; increased blood flow Increased uptake of 24Na

System

Bovine thyroid slices Homogenates of bovine thyroid Homogenates of bovine and canine thyroid after TSH in vivo Male hypophysectomized or thyroxin-suppressed rats, in I’ivo

Reference Pastan er af. (1966) Pastan and Katzen (1967) Zor et a/. (1969)

Wollman et al. (1964); Wetzel et al. (1965); Seljelid (1967a-e); Ekholm and Smeds (1966)

Ekholm el a/. (1975) Canine thyroid slices after TSH in vivo

Field er al. (1%3); Dumont and Rocmans (1964)

Male, thyroxin-suppressed rats

Clayton and Szego (1967)

Chicks

Solomon (1961)

20 minutes

1-6 hours

W

2 1 hours

4

24 hours

48 hours

Increased plasma levels of hormonal iodine and of iodide from preformed hormone; iodide organification Increased permeability [I4C]uridine Colloid droplet digestion after lysosomal fusion Onset of increase in water content Increased permeability [14C]amino acids Increased incorporation 3*P into phospholipid Thyroglobulin maturation 15 S, 19 S Increased incorporation [14C]uridine into RNA; increased net RNA (6 hours) Increased cell height, nuclear volume Elevation of water content Increased incorporation isotopic amino acids into protein (earlier effects may be masked by proteolysis) Thyroglobulin synthesis Increased DNA content Increased mitoses ~~

Thyroid venous effluent in dogs

Rosenberg et a!. (1965)

Chicks Male hypophysectomized or thyroxin-suppressed rats in uiuo Chicks Chicks Guinea pigs

Creek (1965) Seljelid (1967b)

Male, thyroxin-suppressed rats Chicks

Cavalieri and Searle (1967) Creek (1965)

Thyroxin-suppressed dogs (thyroid perfusion) Male, thyroxin-suppressed rats Guinea pig thyroid slices after TSH in uivo

Nhve and Dumont (1970a) Clayton and Szego (1967) Raghupathy et al. (1963)

Hypophysectomized rats Guinea pigs Guinea pigs

Pavlovic-Houmac et al. (1967) Ekholm and PantiC (1963) Gedda ( 1960)

Solomon (1961) Klitgaard et al. (1965) Kerkof and Tata (1967)

~

"Reprinted, with minor alterations, by permission from Szego (1975),wherein the crtutions may befound. See also, Freinkel(1964); Field (1968,1975);Spiro (1980);Nitsch and Wollman (1980);Tata (1980);these latter citations refer to present bibliography.

38

CLARA M. SZEGO AND RICHARD J. PIETRAS TABLE V TRANSFORMATION“ TIMECOURSEOF SMALLLYMPHOCYTE Time after mitogen application

Plasma membrane 5 5 minutes

5-40 minutes

Event

PHA binding Activation of surface-membrane Na+ ,K+-ATPase Mitogen capping (including TMV. Con A, anti-H-2) Development of fluorescein- and ionpermeable intercellular junctions Increased influx of isotopically labeled Pi Uridine 3-0-Methyl glucose Increased 32Pi incorporation into phosphatidylinositol Increased influx of K’ Ca2 cu-Aminoisobutyric acid +

Increased levels of CAMP cCMP Integration of levels of the above cyclic nucleotides with [Ca2+ 1 Lysosomal-vacuome system 10 minutes Transforniation antagonism by inhibitor of cathepsin-like protease 20-30 minute5 Iricrcascd uptake of Neutral red S. fyphimurium endotoxin Reduced structural latency of lysosomal 30- 120 minutes hydrolases Breakdown of RNA Increased total acid phosphatasc activity 4-5 hours Enlargement and increased pglycerophosphate permeability Transformation inhibition by lysosomal (and other membrane) "stabilizers"

Reference

Kay (1971); Mendelsohn el ul. (1971) Quastel and Kaplan (1970), Lauf (1975) Loor et al. (1972); Raff and de Petris (1973) Hulser and Petcrs (1971), Sellin et al (1974) Cross and Ord ( 197I ) Peters and Hausen ( 1971 a) Peters and Hausen (197 I b) Fisher and Mueller (1971)

Quaatel et al. (1970) Allwood et al. (197 I ) Mendelsohn et al. (1971); van den Berg and Betel (1971) Smith er ul. (1971), Webb ~t d. ( 1973) Hadden el ul. (1972) Whitfield et al. (1973)

Saito er al. (1973)

Hirschhorn et a/. (1968) Robineaux et ul. (1969) Hirschhorn et al. (1968) Cooper and Rubin (1965) Gillissen and Mecke (1973) Allison and Mallucci (1964a) Hurvitz and Hirachhorn ( I 965)

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

39

TABLE V (Continued) Time after mitogen application Nuclear < 10 minutes

10 minutes

15 minutes

20 minutes 30-60 minutes 2-4 hours

24-36 hours

General cellular 2 hours 2 hours + 72 hours

Event

Increased AO binding of deoxyribonucleoprotein Perinuclear localization of [ '2sII]anti-HLA2; intranuclear at 24 hours Perinuclear localization of antigen (immunofluorescence); nuclear at 60 minutes Increased activity of histone phosphatase Nuclear localiztion of [3H]PHA Increased histone acetylation Activity of histone kinase Phosphorylation of nucleoproteins Labeling of RNA from [3H]uridine Nonhistone chromatin proteins DNA-dependent RNA polymerase activity (low salt) DNA-dependent RNA polymerase activity (high salt) DNA polymerase activity Thymidine incorporation into DNA

Increased incorporation of [3H]leucine into protein Accentuated RNA metabolism Mitosis

Reference

Killander and Rigler (1965) Lewis et a!. ( 1 974) Coons et a/. (1950)

Cross and Ord ( I 97 1) Stanley et al. (1971) Pogo et a/. (1966) Cross and Ord (1 97 1 ) Kleinsrnith e t a / . (1966) Kay and Cooper (1969) Levy eJ al. (1973) Handmaker and Graef (1970)

Loeb and Agarwal (1971) MacKinney et al. (1962)

Neiman and MacDonnell (1970) Lucas (1971) Nowell (1960)

"Reprinted with minor alterations, by permission, from Szego (1975), wherein all but the following cirarions muy he,fuuad: Quastel and Kaplan (1970); Lauf (1975); the latter are cited presently. See also, Reilly and Ferber (1976); Hume and Weidernann (1980); Udey and Parker (1980); Sidman (1981); Becker et al. (1981).

that a host of metabolic events, grouping themselves into apparent classes, requires integration if a potentially meaningful interpretation of such reaction sequences is to emerge. The list of phenomena that must be accounted for is likewise extensive. viz.: a. Recognition and capture of (hormonal) agonist ( H ) by mutual complementarity of latter with presumptive receptor ( R ) protein intrinsic to the plasmalemma b. Propagation of the primary event: ( 1 ) Adaptive change in surface organization and its relation to signal trans-

40

CLARA M . SZEGO AND RICHARD J . PIETRAS

duction and enhanced exchanges of cellular components with the extracellular fluid. ( 2 ) The H : R entry mechanism. ( 3 ) R activation and/or transformation to a modified, generally diminished structure, R ’ . (4) H:R’ entry into the nuclear compartment concomitantly with changes in numerous metabolic activities in nucleus and cytoplasm, many of which undergo progressive augmentation in rate. (5) Within the nucleus. (a) Interaction of H : R ’ , or possibly each component, individually, or perhaps only one or the other, with acceptor sites, protein or DNA, in chromatin. (b) Modification of the higher order of DNA structure. (c) Access of appropriate polymerase to specific sites destined, by base sequence and localization of modulatory protein factors, for transcription. (d) Processing of primary RNA transcript(s). (e) Emergence of mature RNA product(s) into the cytoplasm; degradation in situ of certain by-products. (6) In the cytoplasm. ( a ) Translation-with all the contributory fuctors required to be present at the appropriate concentrations: the amino acid mix, together with the relevant activating enzymes and tRNA; the ribosomal complement in functionally active state, along with the requisite initiation, elongation, and termination factors; and the specifying programs inherent in mature mRNA. (b) Changes in rates of degradation of preexisting or nascent proteins and other macromolecules. (7) Depletion of surface-oriented R (“down-regulation”), generally in apparent correlation with H levels. ( 8 ) Repletion of R , and “migration” to, and insertion in, the plasmalemma. The above, by no means intended to be inclusive, are indeed a challenging agenda.

B. THERELEVANTPROPERTIES OF LYSOSOMES Cogent evidence has now accumulated that implicates lysosomal functions in the reception, transduction, and propagation of a wide variety of effectors in diverse cell types. The grounds for this proposal (cf. Szego, 1971a,b; Szego ei a l . , 1971) are inherent in the characteristics of lysosomes, a most heterogeneous and pluripotent class of organelles. Therefore, before undertaking detailed con-

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

41

sideration of the evidence linking the specific properties of lysosomes to the expression of agonal phenomena, it seems appropriate to summarize the unique properties that render this organelle potentially capable of subserving a substantial number of the functions outlined above. More extensive consideration of lysosomal participation in the normal metabolic economy, as well as under pathological conditions, is available elsewhere (Dingle and various co-editors, 1969, 1973-1975; Jacques, 1972; Dean and Barrett, 1976; von Figura et al., 1980; Callahan and Lowden, 1981; Glaumann et a l . , 1981). Lysosomes constitute a major component of the vacuome, a complex system of intracellular vesicles and structures wherein it was proposed that anabolic and catabolic cell functions are segregated (cf. de Duve, 1969). The anabolic segment of the vacuome consists of rough and smooth endoplasmic reticulum (ER), together with the Golgi apparatus. Proteins destined for secretion, as well as those that will ultimately reside in the plasma membrane, Golgi apparatus, or lysosomes, are all found at early stages of their biosynthesis in ER and appear to pass either through or adjacent to the Golgi apparatus during posttranslational maturation, if any. In cells endowed with the capacity to export certain protein products, secretory proteins are packaged in granules for exocytosis (Palade, 1975), whereas certain membrane proteins appear to associate with clathrincoated vesicles for transport to Golgi and/or plasma membranes (Pearse, 1975; Rothman and Fine, 1980). In contrast, lysosomal enzymes are segregated in primary lysosomes (cf. Hasilik and Neufeld, 1980a,b; Sly, 1980). The latter constitute one component of the vacuolar apparatus (de Duve and Wattiaux, 1966), the second major segment of the vacuome, and that which mediates the catabolism of endogenous and exogenous molecules (de Duve, 1969). Extracellular material taken up in course of invagination of the plasma membrane results in the generation of phagosomes or endocytotic vesicles in the cell interior. The latter vesicles then generally fuse with a given fraction of the primary lysosomal population, yielding secondary lysosomes, which are considered sites of catabolic activity. The lysosomal apparatus (cf. de Duve and Wattiaux, 1966; Bainton, 1981) comprises a dynamic system of primary and secondary lysosomes, autophagosomes (containing sequestered intracellular materials), heterophagosomes (containing sequestered extracellular materials), multivesicular bodies (composed of compound vesicles disposed in an amorphous matrix), and residual bodies (containing incompletely degraded materials). Discharge of the contents of either endocytotic vesicles or lysosomal structures into the extracellular space by exocytosis may occur in some instances (de Duve, 1969). 1, Pathways of Uptake of Nutrient and EfSector Substances into the Vacuolar Apparatus Extracellular materials appear to enter cells either by a process of permeation or by incorporation within membrane-limited vacuoles or vesicles. The former pathway involves penetration of a given substance through the plasma membrane

42

CLARA M. SZEGO A N D RICHARD J . PIETRAS

by passive or facilitated diffusion or by active transport (cf. Stein, 1967; Diamond and Wright, 1969; Dietschy, 1978). The alternative pathway is generally termed endocytosis. several varieties of which have been distinguished. However, it is important to note that these two pathways are not mutually exclusive for uptake of a given substance. Several investigators have presented evidence for simultaneous transport of a given molecular species by passive permeation, as well as by specific endocytosis (cf. Thomson, 1978; Brown and Goldstein, 1979; Szego and Pietras, 1981). The several known and putative forms of endocytosis are represented in schematic form in Fig. 4. Two major classes of endocytotic uptake can be distinguished. Phagocylosis occurs mainly in specialized cells and can be defined as the process of ingestion of solids of relatively large size (e.g., erythrocytes, latex spheres, carbon particles) with little concomitant uptake of fluid (Siiverstein et al., 1977). On the other hand, pinucytusis is a more ubiquitous process exhibited by virtually all cells and leads to the interiorization of fluid and solutes, together with small particles (cf. Simson and Spicer, 1973; Sly, 1980). Pinocytosis may be nonselective (i .e., fluidphase) or selective (adsorptive or receptor-mediated) (Jacques, 1969a) and may result in the formation of intracellular vesicles of 300-1000 nm in diameter (macrupinucytusis) or of about 70 nm in diameter (nzierc~,pinocytosis;cf. Allison and Davies, 1974b; Pratten et al., 1980; Sly, 1980). Some micropinocytotic vesicles bear a smooth-surfaced limiting membrane (Palade, 1960), while others, with diameters ranging from 50 to 250 nm, exhibit a filamentous coat on their cytoplasmic surfaces and appear to arise from specialized regions of the plasma membrane termed “coated pits” (cf. Pearse, 1980). The coating of the latter vesicle is a lattice formed by a single protein species, clathrin (Pearse, 1976), that is capable of self-assembly from its constituent subunits into a symmetrical, trimeric cage-like structure without participation of additional proteins (cf. Kirchhausen and Harrison, 1981). A mongrel form of pinocytotic vesicle, recently christened “receptosome” by Willingham and Pastan (1980), is a smooth-surfaced organelle of 150-300 nm in diameter and appears to be formed by interiorization of plasmalemmal coated pits, with presumedly concomitant shedding or exclusion of coat material from the vesicle upon its interiorization (cf. Willingham et a/., 1981a). However, the likelihood of such an “uncoating” process has been discounted recently on the grounds of the extremely rapid time course (of the order of seconds) that would be required (Willingham and Pastan, 1981). Finally, limited data presently available suggest that some cytoplasmic vesicles with average diameters of about 70 nm may constitute elements of a fused chain of branching, permanent or semipermanent invaginations of the plasma membrane (Simionescu et al., 1975; Bundgaard et al., 1979). The latter workers proposed that such a racemose system of vesicles may provide a hitherto unrecognized pathway for intracellular penetration of given solutes.

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

43

PHAGOCYTOSIS: VACUOLES, dio > l p m [ P o r t i c l e s ]

MACROPINOCYTOSIS: VESICLES, 3 0 0 - 1 0 0 0 nm [Ferritin]

RECEPTOR-MEDIATED MACROPINOCYTOSIS: [ H L A - A n t i g e n ]

I

CP

RECEPTOR-MEDIATED PINOCYTOSIS VIA COATED P I T : 50-250 n m [LDL-cholesterol] RECEPTOR-MEDIATED PINOCYTOSIS VIA COATED PIT 8 'RECEPTOSOME': 1 5 0 - 3 5 0 n r n [ a z - M G ] MICROPINOCYTOSIS

70 nrn

RACEMOSE VESICULATION: 50-200nm; DIFFUSION

U

1

I

I

2

5

15-30

APPROXIMATE T I M E (rnin) FIG. 4. Schematic representation of pathways for the internalization of extracellular agonists, as modified from Geisow (1980). Examples, within brackets. Observations, both descriptive and quantitative, upon which this generalized scheme for the several classifications of endocytotic activity is based, are as follows: phagocytosis (Metchnikoff, 1883); macropinocytosis (Lewis, 1931); micropinocytosis (Palade, 1960; Casley-Smith, 1969; Casley-Smith and Chin, 1971); racemose vesiculation (Bundgaard et a [ . , 1979); and associated receptor-mediated pathways (Anderson et ul., 1977; Pearse, 1980; Willingham and Pastan, 1980; Montesano et d . , 1982). (Cf. also Jacques, 1969a; Allison and Davies, 1974b; Szego, 1978; Herzog, 1981.)

Extracellular materials and surface membrane components internalized by endocytosis appear to be directed along multiple routes in the cell interior (Jacques, 1972; Farquhar, 1981a,b; Herzog, 1981). In secretory cells, observations with electron-dense tracers reveal two major endocytotic pathways: (1) direct route to lysosomes, from which some material is subsequently transferred to the stacked Golgi cisternae; and (2) direct route to the Golgi apparatus (cf.

44

CLARA M. SZEGO AND RICHARD J . PIETRAS

Farquhar, 1981a,b; Herzog, 1981). Factors that appear to regulate the movement of incoming vesicles to lysosomes or to Golgi cisternae include composition, charge, and size of the tracer, as well as the type and physiological state of the given cell (Herzog, 1981). In highly differentiated glandular cells, and probably in most eukaryotic cells (cf. Chapman-Andresen, 1977), this process appears to provide a mechanism to salvage and reutilize membrane components. However, it apparently also provides direct access of agonists, as well as of macromolecules integral to given membranes (e.g., receptors, enzymic moieties), to critical biosynthetic and degradative compartments of the cell (cf. also, Haimes et al., 1981; Goldfischer, 1982). Further discussion on the traffic patterns of incoming materials may be found in Section II,B,S,a and succeeding sections of this article. A clear mechanismic distinction is evident between, on the one hand, phagocytosis and macropinocytosis and, on the other hand, micropinocytosis and coated vesicle formation (Allison, 1973; Szego, 1978; Ockleford and Munn, 1980; Kusiak et al., 1980; Szego and Pietras, 1981). Although the former processes are strongly depressed by inhibitors of glycolysis or oxidative phosphorylation (cf. Allison and Davies, 1974a,b; Ockleford and Munn, 1980), the formation of microvesicles and coated vesicles is found generally not to require direct input of metabolic energy (Casley-Smith, 1969; Nagura and Asai, 1976; Ockleford and Munn, 1980; however, cf. Munthe-Kaas, 1977). Some investigators (Allison and Davies, 1974a,b; Anderson et al., 1977) report that micropinocytosis is inhibited at low temperature, as are other forms of endocytosis, but others find that the formation of smooth and coated microvesicles is not markedly reduced at 4°C (Casley-Smith and Day, 1966; Nagura and Asai, 1976; however, cf. Ockleford and Munn, 1980). Inhibitors of microtubule assembly (e.g., colchicine) generally show little effect on the several classes of endocytosis (Bhisey and Freed, 1971; Ockleford and Munn, 1980; Kusiak et al., 1980). In contrast, cytochalasin B, a drug which depresses actin-based motile processes such as are integral to the function of microfilaments (Wessells et al., 1971), inhibits phagocytosis and macropinocytosis (Allison, 1973; Ockleford and Munn, 1980) but elicits only slight (Munthe-Kaas, 1977) or no (Allison and Davies, 1974a; Nagura and Asai, 1976) inhibition of micropinocytosis involving either smooth or coated vesicles. Thus, the generation of smooth and coated microvesicles from plasma membrane emerges as a process less dependent on metabolic energy supply and subplasmalemmal mechanoeffector systems than other forms of endocytosis. Evidence for the premise that specific binding of certain macromolecules to plasmalemmal receptors must precede uptake into a given endocytotic transport system originated from studies in several areas. These include (1) selective transport of immunoglobulin in the fetal yolk sac and neonatal intestine (Anderson and Spielman, 1971; Wild, 1973); (2) receptor-mediated uptake of yolk

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

45

protein by the oocyte (Roth and Porter, 1964; Roth et al., 1976); (3) specific entry of transcobalamin 11-vitamin B, complexes into kidney and liver cells and into fibroblasts (Newmark et al., 1970; Pletsch and Coffey, 1971; YoungdahlTurner et al., 1978); (4) selective hepatic clearance of modified plasma proteins (Ashwell and Morell, 1974); and (5) receptor-mediated endocytosis of cholesterol-lipoprotein complexes in fibroblasts (Anderson er al., 1977). A plethora of corresponding observations for hormones and other effectors is likewise available and allows for evaluation of the cogency and generality of this transport process (see succeeding sections). It is clear that one means of triggering regional internalization of the cell surface (i.e., adsorptive or receptor-mediated endocytosis) is the ligand-induced redistribution of integral proteins into patches and clusters in the plasmalemma. The mechanism for such “provoked internalization” (Szego, 1978) is believed to be related to the stress of deformation of the membrane as a consequence of regional clustering of intrinsic ligand-decorated protein, with resultant local change in permeability to some critical factor (e.g., Ca2+), which, in turn, may activate contractile elements in the subplasmalemmal cytoskeleton (Singer, 1975, 1976; Edelman, 1976; Szego and Pietras, 1981). Microfilaments and perhaps other less well-defined mechanoeffector elements are generally considered to play an active role in ligand-induced clustering of surface components (Rutishauser and Edelman, 1978; Singer et al., 1978). Some investigators suggest that microtubules are also involved in this process (Ukena and Berlin, 1972; Albertini and Clark, 1975; Rutishauser and Edelman, 1978) but others dispute this contention (de Petris, 1974; Singer et al., 1978). Although agonists of low molecular weight, viz. triiodothyronine (Cheng et al., 1980) and estradiol-17P (Szego and Pietras, 1981), promote a redistribution of membrane-associated proteins on specific recognition, a related mechanism by which cells endocytose ligand-receptor complexes may be better adapted to the function of agonists that are not multivalent. For example, surface receptors for cholesterol-lipoprotein complexes in fibroblasts appear to be confined largely to coated pit structures, which constitute an estimated 2% of the total surface area of the plasma membrane (Anderson et al., 1977). Endocytosis resulting from interaction of ligand with its specific receptor so localized is presumably not triggered by ligand-induced clustering of membrane receptors, since the latter were aggregated prior to ligand exposure. Such preaggregation of membrane receptor proteins m-ay be a consequence of the proposed continuous flow of plasmalemmal lipid and protein constituents toward coated regions of the surface membrane (Bretscher, 1976; Pearse, 1980). Under such circumstances, the stimulus for membrane deformation leading to coated vesicle formation may be derived from the ligand-receptor interaction per se, from alteration in the selfassociation (Kirchhausen and Harrison, 1981) or conformation of coat protein (i.e., clathrin) molecules, or, in part, from both processes, especially if the

46

CLARA M . SZEGO AND RICHARD J. PIETRAS

clathrin lattice at the inner membrane face is coextensive with receptor aggregates at the external surface (Kanaseki and Kadota, 1969; Ockleford and Munn, 1980). Neither phagosomes nor macro- and micropinocytotic vesicles contain a random complement of cell surface macromolecules (Tsan and Berlin, I97 1 ; Pearse, 1975; Birchmeier er al., 1979; Suzuki and Kono, 1979; Willinger ct a/., 1979). It is not known whether this is attributable to the occurrence of sites on plasma membrane destined for preferential internalization or to the function of some active but undefined molecular exclusion mechanism (cf. Bretscher, 1976; Pearse and Bretscher, 1981). In any event, newly formed endocytotic vesicles exhibit saltatory motion, in course of which certain of their population undergo fusion, predominantly with those organelles of the lysosomal system that are appropriately disposed (cf. Allison, 1973; de Petris, 1977; Muller et a/., 1980a,b), or marked in some as yet undetermined manner. Some micropinocytotic vesicles may also gain access directly or indirectly to other cellular compartments including the nucleus (cf. Szego, 1975; Y.-J. Schneider et al., 1978; Szego and Pietras, 1981), the Golgi apparatus (Bergeron et al., 1979; Willingham and Pastan, 1980), and the opposing plasma membrane (Allison and Davies, l974b). Although the thermal energy needed for niicrovesicular movement appears to be supplied solely by Brownian motion, the rate of this linear translocation process is extremely rapid (Casley-Smith, 1969; Casley-Smith and Chin, 1971; Green and Casley-Smith, 1972; however, cf. Ockleford and Munn, 1980, and Section II,B,S,a). Interestingly, the clathrin lattice of coated microvesicles is apparently partially or totally shed before fusion of its phospholipid bilayer core with a given membrane (Douglas, 1974; Anderson et al., 1977). Energy requirements for the shedding process are not known, but Ockleford and Munn (1980) suggest that activity of a Ca2 -dependent ATPase associated with such vesicles (Blitz et al., 1977) may be contributory. +

2. Composition and Organization of Lysosomes a. Enzymic Constituents. The pivotal biochemical studies of de Duve and colleagues led to the initial characterization of lysosomes as membrane-limited intracellular organelles sequestering acid hydrolases (cf. de Duve and Wattiaux, 1966; de Duve, 1969; Bainton, 1981). More than 70 different enzymes with a wide variety of substrate specificities are now known to occur in lysosomes of one or more cell types (cf. Barrett and Dean, 1976; Barrett and Heath, 1977). The biocatalytic properties of lysosomal hydrolases are well known to vary with assay conditions, such as the type of buffer (Otto, 1971) and the nature of the substrate (Bohley et al., 1971). Nevertheless, these hydrolases generally exhibit optimal activity at acid pH. However, some lysosomal enzymes are active at neutral or alkaline pH (Hugon and Borgers, 1967; Davies et al., 1971; Bainton, 1973; McDonald and Ellis, 1975; Dean and Barrett, 1976; Eeckhout and Vaes,

LYSOSOMAL FUNCTIONS IN CELLULAR ACTIVATION

47

1977; Hagiwara et al., 1980; Britz and Lowther, 1981; Collins and Wells, 1982, 1983), especially in their membrane-bound form (see Table XV and Melloni et al., 1982a,b). In addition, there is recent evidence for the sequestration of nonhydrolytic enzymes in lysosomes (Mraz et al., 1976; Dousset et al., 1979; Griffiths and Lloyd, 1979; Entenmann et al., 1980; Wells et al., 1981; Geller and Winge, 1982; Collins and Wells, 1982, 1983). Most, if not all, lysosomal enzymes, including cathepsin B (Towatari et al., 1979; Seeler and Szego, 1984), are glycoproteins (Dean, 1975a; Dean and Barrett, 1976). Variation in the classes, distribution, and numbers of these charged carbohydrate moieties may contribute to the occurrence of multiple forms of enzymes with very similar substrate specificities (cf. Dean, 1975a). In turn, variation in classes, distribution, and numbers of such moieties may underlie the differential responses of certain hydrolases, e.g., cathepsin B, toward organic and inorganic modulators as a function of cellular origin of the enzyme (cf. Szego et al., 1976). Moreover, constitutive glycosylation of lysosomal enzymes appears to contribute a critical recognition function for channeling these organellar components to appropriate intracellular and/or surface membrane sites of given cells (see Section II,B,4). b. Heterogeneity of Lysosomes. The initial studies of lysosomes by de Duve and co-workers revealed a remarkable heterogeneity of rat liver lysosomes with respect to their density and size (i.e. calculated diameters of 0.25 to 0.8 pm; de Duve, 1969). However, only minor differences were found in the distribution of acid hydrolases of various subcellular fractions separated by differential pelleting. From such findings arose the view, still widely accepted, that, apart from isolated examples of specialized lysosomes in some cell types (e.g., the acrosome of spermatozoa), lysosomes do not exhibit significant biochemical or enzymic heterogeneity. However, subsequent studies of lysosomal populations of rat liver, as well as those of certain other organs and homogeneous cell lines, have revealed significant differences in the relative enrichment of acid hydrolases among subcellular fractions separated by isopycnic or rate-zonal centrifugation (cf. Davies, 1975; Sloane and Bird, 1977; Dobrota et al., 1979; Tanaka, 1979; Knook and Sleyster, 1980; Rome et al., 1979; Radzun et al., 1980). These studies provide evidence of at least two populations of lysosomes with different densities and with qualitatively different enzyme contents, not only in rat liver, wherein cellular heterogeneity may be a contributory factor (Knook and Sleyster, 1980), but also in Chinese hamster ovary fibroblasts (cf. Davies, 1975) and other cultured cells (cf. Milsom and Wynn, 1973), which constitute homogeneous populations. More recent studies using ultrdcytochemical (Uchiyama and von Mayersbach, 1981) and X-ray microanalytical (BAcsy, 1982) techniques tend to confirm the latter findings. The distinct enzymic heterogeneity of lysosomes implies that packaging of enzymes in lysosomes is not a uniform process but a variable function, probably dependent on the rates of synthesis or availability of individual hydrolases at

48

CLARA M. SZEGO AND RICHARD J . PIETRAS

packaging “stations” (cf. Davies, 1975; Dean and Barrett, 1976). Differential rates of synthesis of individual lysosomal hydrolases, a well-characterized response of specific target cells to hormonal stimulation (cf. Table VI), conceivably could result in the formation of primary lysosomes relatively enriched in specific activities of given hydrolases. Alternatively, hydrolase content might be selectively altered at the level of the smooth ER or GERL (see examples in Davies, 1975; Paigen, 1981), regions in which apparent transitory accumulation of lysosomal enzymes has been reported (cf. Brandes and Anton, 1969; Sloane, 1980;and see below). Moreover, as emphasized by Davies (1975), heterogeneity of structural stabilities or degradation rates of lysosomal hydrolases probably prevails in vivo, thereby leading to accentuation of differences in enzyme content (cf. Nemere and Szego, 1981b). Indeed, data on the ontogeny of capacities for synthesis, as well as for degradation, of given lysosomal constituents and even of the assembled organelles themselves (Quintart et al., 1979a; Lodish et al., 1981) TABLE VI REPRtSENTATIVE EXAMP1,ES O F DELAYEDCHANGES ELICITEDB Y AGONISTSIN Ac-TIVITIES O R CONCEN’IRATIONSOF LYSOSOMAL COMPONENTS“ Agonist Pcptide hormones ACTH

Chorionic gonadotropin

Follicle-stimulating hormonc Glucagon Growth hormone lnsulin Luteinizing hormone

Parathyroid hormone Prolactin Kclaxin

THE

TOTAL

Reference

Szab6 e r a / . (1967); Dominguez et a / . (1974); Kostulak (1977); Laychock r / a/. (1977); Mattson and Kowal (1978); Trzcciak et a/. (1979); Mattson and Kowal (1980) Dimino and Reecc ( 1 973); Cajander and Bjersing (1975, 1976); Dimino e t a / . (1977); Elfont ri ( I / . ( 1977) Elkington and Blackshaw (1973, 1974); Zoller and Wcisz ( 1980) Gilder et a/. (1970); Mortimore and Ncely (1975) Steinetz el a / . (1965); Swank (1978); Huhhard and’ Liberti (1981. 1982) Wildenthal (1973); Mortimore and Neely (1975); Hcdly and Dinsdale ( I 979) Elkington and Blackshaw (1973, 1974); Boer ri a/. (1976); Strauss et ti/. (1978); Witkowskd (1979); Zoller and Weisz (1980); cf. also Okazaki et u / . ( 1977) Hara and Nagatsu (1968); Vaes (1969); Eilon and Raisz (1978) Ciiunta ef a/. (1972); 1-ahav ei trl. (1977) Steinetz rt a/. (1965); Manning er u / . (1967); McDonald and Schwabe (1982)

TABLE VI (Continued) Agonist Thyroid hormones”

Thyroid-stimulating hormone

Steroid hormones Androgen

Ecdy steroid Estrogen

Gibberellins Glucocorticoids

Reference Fox (1973); Farooqui et al. (1977); DeMartino and Goldberg (1978); Mandel er a / . (1978); Mori and Cohen (1978); Coates et al. (1978, 1982); DeMartino and Goldberg (1981); Severson and Fletcher (1981) Ekholm and Smeds (1966); Seljelid et al. (1971); Bigazzi and DeGroot (1973); Starling et al. (1978)

de Duve et al. (1962); Lasnitzki et al. (1965); Males and Turkington (1971); Elkington and Blackshaw (1973); Kochakian and Williams (1973); Ban et al. (1974); Elkington and Blackshaw (1974); Iela er al. (1974); Serova and Kerkis (1974); Brandt et al. (1975); Kamble and Mellors (1975); Milone and Rastogi (1976); Fischer and Swain (1978); Moore et al. (1978); Swank (1978); Tenniswood et al. (1978); Blecher and Kirkeby (1979); Koenig et al. (1980a,b); Goldstone et al. (1981); Watson et al. (1981) Radford and Misch (1971); van Pelt-Verkuil (1979) Fishman and Fishman (1944); Harris and Cohen (1951); Beyler and Szego (1954); de Duve er al. (1962); Steplewski and WaroAski (1973); Banon et al. (1964); Watanabe and Fishman (1964); Lasnitzki et al. (1965); Woessner (1969); Smith and Henzl (1969); Schiebler et al. (1970); Platt (1972); Ban et al. (1974); Moulton (1974, 1982); Nozawa et al. (1974); Wolinsky et al. (1974); Serova and Kerkis (1974); Baron and Esterly (1975); Boshier and Katz (1975); Briggs and Briggs (1975); Gustavii (1975); Kamble and Mellors (1975); Katz et al. (1976); Zachariah and Moudgal (1977); Moore et al. (1 978); Jaccard and Cimasoni (1979); Sengupta et al. (1979); Witkowska (1979); Elangovan and Moulton ( 1980); Sloane ( 1980) Gibson and Paleg (1972, 1976); Gonzilez (1978) de Duve et al. (1962); Weissmann and Thomas (1964); Lasnitzki et al. (1965); Nakagawa er al. (1968); Abraham et al. (1969); Caruhelli and Griffin (1970); Bingham et al. (1971); Bowness and Barry (1972); Bourne et al. (1973); Chertow et al. (1973); Kamble and Mellors (1975); Brehier et al. (1977); Kasukabe et al. (1977); Clarke and Wills (1978); Mandel et al. (1978); Moore et al. (1978); Bagwell and Ferguson (1980); MacDonald et al. (1980) (continued)

50

CLARA M. SZEGO AND RICHARD J. PIETRAS TABLE VI (Continued) Agonist

Progecternne

Testosteronc Vitamin D Othcr effectors Chemical carcinogens

Juvenile hormone Phytohemagglutinin Prostaglandin Fzrr Viruses

Vitamin A

Reference Harris and Cohen (1951); Steinetz CI a/. (1965); Manning rt a / . (1967); Moulton (1974, 1982); Serova and Kerkis (1974); Bazer ef a / . (1975): Roberts ~t id. (1976); Sloane and Bird (1977); Hoversland and Weitlauf (1978); Paavola (197X); Elfont e l ol. (1979); Lucas (1979); Witkowska (1979); Elangovan and Moulton (1980); Sloane ( 1980); Tyree ef a / . ( 19x0) McCluer et a / . (19x1) Lerncr (19x0); Davis and Joncs (1982)

Nodes and Reid (1963): Slater and Grecnbaum (196s); Flaks (1970);Pokrovsky el a / . (1972); Schulze (1973); Berg and Christoffersen (1974); Hultherg and Mitelman (1977); Pietras (1978) Bccl and Feir (1977); Koesterer and Feir (1980) Hirschhom ef a/. (1965, 1967): Konig et d.(1973) McClellan t i d.(1977) Allihon and Sandelin (1963); Wolff and Bubel (1964); Allison and Mallucci (1965): Flanagan (1966); Hotham-Iglewski and Ludwig (1966); Allison and Black (1967); Thacore and Wolff (1968); La Placa el ul. (1969); Greenham and Poste (197 I ) ; Postc (1971 h); S y l v h e/ a / . (1974); Lockwood and Shier (1977) Lucy eta!. (1961); Fell and Dinglc (1963); Poste (I97 1a)

90% of the NGF bound to receptors that were associated with Tnton-insoluble cytoskeletons Colchicine-induced MT depolymerization stimulated DNA synthesis to 75% of the maximum level induced by thrombin. Taxol stabilization of MTs inhibited thrombin stimulation of DNA synthesis by 30% Colchicine inhibited mitogenic stimulation by insulin and by EGF in sparse cultures of mouse or chick, but not 3T3, fibroblasts. Colchicine itself was mitogenic in confluent cultures of embryonic chick fibroblasts

Conclusions A cytoskeletal protein may

Reference Vale and Shooter (1982)

act as an effector molecule in modulating receptor properties

MT depolymerization is involved in growth factor stimulation of cell proliferation

Crossin and Carney (1981)

Effects of MT disruption on hormone-induced cell growth are dependent on the cell type as well as on the density of the cultures

McClain and Edelman ( 1980)

Colchicine treatment produced a time- and temperature-dependent decrease in insulin binding

Isolated rat hepdtocyteS

Glucose oxidation; 2-deoxy-nglucose transport

Isolated rat adipocytes

Biochemical

Cultured Reuber hepatoma (H-35) cells

Tyrosine aminotransferase (TAT)

Colchicine inhibited both basal and insulin-stimulated glucose oxidation and 2-deoxy-~-glucose transport Insulin promoted the assembly of MTs. Insulin-stimulated lipid and glycogen synthesis, but not glucose oxidation, were inhibited by colchicine Cytochalasin B inhibited the induction of TAT by insulin or cortisol, but not by db-CAMP

Colchicine may impair the transport of unoccupied (recycled or newly synthesized) receptors to the plasma membrane Effects of colchicine are due to an action at the plasma membrane

Whittaker et al. (198 1)

Capacity of insulin to “direct” glucose metabolism may be dependent upon MTs

Soifer et al. (1971)

Cytochalasin B may prevent TAT induction by altering the MF network. CAMP may promote MF assembly or stabilize MFs, and thus antagonize the effects of cytochalasin B

Butcher and Perdue (1973)

Cheng and Katsoyannis (1975)

(continued)

TABLE XVIII (Continued) Actmist

Cell type

Criteria

Observations ~

Intrrfcron

PTH

Cultured human fibroblasts

LM. IF

Goldfish xanthophores

LM

Bone and CHO cells

Tubulin content. by colchicine binding assay

~~~

Conclusions

Reference

~~~~

Interferon treatment increased the number of actin filaments per cell. but did not affect MT or IF number: the rate of cell locomotion. amount of membrane ruffling. and saltatory movement of intracellular granules were all decreased Carotenoid-containing SER dispersed in response to MSH and aggregated in response to epinephrine. Cytochalasin B inhibited dispersion and colchicine inhibited aggregation The degree of tubulin polymerization was affected by the temperature of cell incubation, but hormoneinduced changes in morphology were not associated with changes in polymerization. However, MF distribution was altered by hormone treatment

Interferon inhibition of cell proliferation may be mediated by cytoskeletal and plasmalemmal alterations

Pfeffer er a!. (1980)

MFs are involved in pigment dispersion and MTs in pigment aggregation

Winchester et a!. (1976)

Suggests that hormone-induced morphological changes are mediated by MFs, not MTs, in cultured bone cells

Beertsen et al. (1982)

Prolactin

Mammary gland cells from pseudopregnant rabbits

Hybridization with [3H]cDNA probes for pcasein mRNA

Rabbit mammary gland explants

Immunoprecipitation with anticasein serum

Rat liver

Distribution of [ 125Ilprolactin and [125I]insulin in density gradients

Rabbit mammary explants

Biochemical

e

N W

Colchicine prevented the prolactin-induced accentuated transcription of the p-casein gene, but not the enhancement of p-casein mRNA stability Three lysomotropic agents, which inhibit degradation of the prolactin-receptor complex, did not prevent prolactin-induced casein synthesis, whereas five MT-disrupting drugs did By 1 hour after colchicine injection, uptake of PRL into light and intermediate Golgi fractions was inhibited. Vincristine was also inhibitory; lumicolchicine was not. Uptake into heavy Golgi and plasmalemmal fractions was unaffected. Colchicine had a similar, but reduced, effect on insulin uptake Griseofulvin, an anti-MT drug, did not prevent prolactin-induced casein synthesis. Also, ['H]colchicine was found to associate with cellular membranes, especially the plasma and Golgi membranes

MTs are involved in the transfer of the prolactin signal to the p-casein gene

Teyssot and Houdebine (1980)

MTs are involved in the mechanism of prolactin action

Houdebine ( 1980)

Prolactin transfer appears to be MT-dependent; insulin transfer less so. Prolactin and insulin may be transferred in different ways

Posner cc al. (1982h)

MTs are not required for prolactin action. However, colchicine binds to and alters the cellular membranes, thus interfering with the mechanism of prolactin-induced casein synthesis

Houdebine et al. (1982)

TABLE XVIII (Con?imed) Agonist

Cell type

Cntena

Observations

Conclusions

The level of membrane-associated actin was increased by TSH treatment. Also, a lysosomal fraction was found to contain a DNase I inhibitor believed to be actin itself Cytochalasin B inhibited the hydroosmotic response to vasopressin. The drug also increased permeability to Na' , CI - , and urea and induced the formation of large intracellular vacuoles Colchicine treatment inhibited osmotic water flow and the formation of intramembrane particle aggregates in response to vasopressin. but only when the colchicine treatment preceded vasopressin stimulation Mucosal microvilli and terminal web of granular cells were lost following vasopressin treatment

Actin association with lysosomes increases in response to TSH and may be involved in directed movement of lysosomes

Dickson er a / . (1979)

Cytochalasin B may interfere with the coupling of fluid transport and solute movement

Davis er al. (1974)

MTs may be involved in the initiation of vasopressininduced responses

J. Muller et al. (1980)

Suggests that vasopressin alters permeability in part by altering cytoskeletal elements in apical and basal regions

DiBona (1981)

TSHc

Bovine thyroid slices

Density gradient fractionation and PAGE of homogenates

Vasopressid

Toad urinary bladder

TEM, biochemical

Freeze-fracture

Granular cell of toad urinary bladder

LM, TEM

Reference

Miscellaneous Con A

Isolated rat adipocytes

Conversion of [U-'%]glucose to 14C02 was measured

1-Methyladenine (maturationinducing hormone) None

Starfish oocytes, stripped of follicle cells

LM, TEM, SEM

Rat erythrocytes

Biochemical

Acetylcholine

Rat soleus muscle

AcCho receptor sensitivity and electrical potential

The ability of Con A to mimic insulin by stimulating glucose oxidation was not blocked by the disruption of MTs and MFs, but was dependent on Con A valence 1-MA induced the formation of spike-like projections, containing bundles of MFs

Interaction of Con A with insulin receptors does not appear to be dependent upon MTs or MFs

Kahn et al. (1981b)

The MF-containing spikes may play a role in the organization of surface-associated 1-MA receptors

Schroeder (1981)

A considerable proportion of adenylate cyclase activity was associated Triton-extracted cytoskeletons

Suggests that hormonal stimulation of adenylate cyclase may be mediated by the cytoskeleton

Sahyoun et a!. (1981a)

Action of colchicine and cytochalasin B on the AcCho receptor is probably not due to MT/MF disruption

Anwyl and Narahashi (1979)

B. Hydrophobic agonistsn Treatment with either colchicine or cytochalasin B altered the neurophysiological properties of the AcCho receptor, but the effective doses were higher than those required for MT or MF disruption

(continued)

TABLE XVIII (Continued) Agonist

Cell type

a-Bgt

Rat and chick muscle

Adrenalineh

Teleost fish melanophores

Ekdysterone

Cultured Drosophila cells

Estrogen

Rat uterus

Criteria

Observations

Binding of [1251]a-A significant number of receptors was retained on Bgt or TMR-athe cytoskeleton following Bgt Triton extraction Cold treatment together with LM, TEM, and HVEM colchicine failed to prevent adrenaline-stimulated granule aggregation Actin content, asActin increased from 4% of sayed by DNase total protein in untreated cells to 9% in cells exI inhibition posed to ecdysterone for 3 days. Globular and filamentous forms of actin increased at parallel rates during the first 2 days, after which the filamentous form predominated Nuclear uptake of Concentrations of 10 - 5 to [3H]estradiol M cytochalasin B did not inhibit translocation of the estrogen- receptor complex to the nucleus. Vincristine did not affect translocation at early times, but did diminish nuclear uptake after 4 hours of preincubation.

Conclusions

Reference

AcCho receptors are intimately associated with the cytoskeleton

F’rives el a!. (1982)

Pigment granule movement is not MT dependent

Schliwa and Euteneuer (1978)

Actin synthesis and polymerization are stimulated by ecdysterone

Couderc et a / . (1982)

MFs and MTs are not required for nuclear uptake of the estrogen-receptor complex

Gorski and Raker (1973)

Water uptake

Nuclear uptake of [3H]estradiol

-

N

-4

Norepinephrine

Erythrocyte

Binding of [3H]estradiol-receptor (E-R) complex

Ehrlich ascites tumor cells

Depolymerized tubulin, by colchicine-binding assay

S49 lymphoma cells

CAMP, by modified Gilman assay

Colchicine inhibited estradiol-stimulated water uptake Colchicine did not inhibit translocation of the estrogen-receptor complex The E-R complex did not bind to erythrocyte ghosts, but did bind with high affinity, and in a time- and temperature-dependent manner, to Triton-extracted erythrocyte cytoskeletons Desensitization of adenylate cyclase to norepinephrine was accompanied by increased tubulin polymerization; no change in actin filament formation was identified Cytochalasin B enhanced the accumulation of CAMP which followed PGE,, isoproterenol, or cholera toxin treatment

MTs may be involved in the mechanism of estrogen stimulation The effect of colchicine on estrogen-stimulated water uptake is not mediated by inhibition of translocation The extrogen receptor may exist as an integral part of the cytoskeletal network

Fujimoto and Mom11 (1978)

MTs are involved in the desensitization process

Kurokawa et a/. (1980)

MFs may regulate the activity of the adenylate cyclase complex

Insel and Koachman (1982)

Kalimi and Fujimoto (1978)

Puca and Sica (1981)

(continued)

Agonist

Cell type

Criteria

Myeloid leukemic cells, nucleated and enucleated

Refercnce

Observations

Conclusions

Both hormones stimulated cAMP formation in MGI+D-' and M G I - D cells, nucleated, as well as enucleated. Colchicine and vinblastine increased the peak of hormone-induced cAMP in nucleated M G I + D + , but not MGI - D . cells Treatment with PGF,, or FGF resulted in an increase in the rate of initiation of DNA synthesis. Anti-MT drugs had a synergistic effect when added within 8 hours of PGF,,, or FGF addition. but the drugs alone had no effect MFs formed bundles within 3 weeks of androgen withdrawal. MT organization remained unchanged

MTs may be involved in both the normal response to hormonal stimuli and the desensitization process

Simantov el (I/. (1980)

.4n intact cytoskeleton ih not required for initiation of DNA synthesis: in fact. cytoskeletal disruption appears to enhance this process

Otto et 01. ( I 979)

As androgen withdrawal induces androgen insensitivity in these cells, it is suggested that androgen binding alters sensitivity via MFs Thyroid hormones may regulate brain development by promoting MT assembly

Yates cr a/.(1980)

-

PGFZU, FGF

3T3 cells

['HIThymidine incorporation

Testosterone

Cultured Shionogi 115 mouse mammary tumor cells

IF

Thyroid hormones

Rat brain

MT polymerization, assayed by turbidimetry

The degree of in vitro MT polymenzation in brain supernatants from hypothyroid rats was less than that seen in control supernatants from euthyroid rats

Francon cr a / . (1977)

Mouac brain

Triiodothyronine (T,)

Miscellaneous Tertiary arnine local anesthetics

Rat liver parenchymal cells

lurine BALBI3T.3 cells

Tubulin-tyrosine ligase (TTL) activity assayed by [?HH]tyrosineincorporation Uptake of [‘2SI]T3 by cells and by isolated plasma membrane vesicles

Brain levels of TTL. an enzyme involved in a-tubulin metabolism, were reduced in hypothyroid neonates Rate of uptake of T3 into isolated cells was decreased by treatment with colchicine or vinblastine: uptake by vesicles was unaffected

Thyroid hormones may regulate brain development enzymatically via TTL

Lakshmanan et a / . (1981)

MTs are involved in plasmalemmal transport process in situ

Rao ef a / . (1981)

IF

Anesthetics inhibited antibody-induced Ig capping. A similar effect was seen following treatment with cytochalasin B or colchicine

IT and MF regulate the mobility of cell surface receptors

Poste et al. (1975)

“Abbreviations: ACTH. adrenocorticotropin; MT, microtubule; RIA, radioimmunoassay; LM, light microscopy; MF, microfilament; TEM, transmission electron microscopy; SEM, scanning electron microscopy; SDS-PAGE. sodium dodecyl sulfate-polyacrylamide gel electrophoresis; IF, immunofluorescence; FSH. follicle-stimulating hormone; CAMP, cyclic adenosine monophosphate; PGE,, PCE, , PGF,,, prostaglandins; LH, luteinizing hormone; PCM, phasecontrast microscopy; hCG, human chorionic gonadotropin: GnRH, gonadotropin releasing hormone; EGF, epidermal growth factor; NGF, nerve growth factor; WGA, wheat germ agglutinin; db-CAMP, dibutyryl cyclic adenosinc monophosphate; SER, smooth endoplasmic reticulum; MSH, melanocyte stimulating hormone; PTH, parathyroid hormone; CHO, Chinese hamster ovary; TSH, thyroid stimulating hormone; Con A, concanavalin A. “Lumicolchicine is an analog of colchicine that does not bind tubulin nor disrupt MTs. .That such extruded organelles may be internalized by fusion with membranes of neighboring cells is clearly a possibility. Thus it is not too far a cry from such observations to the transcellular acquisition of biochemical markers, shed or presented in vesicular form (cf. Doyle et al., 1979; Rando and Bangerter, 1982) between cocultivated cells, even when the two cell classes are heterophylic (e.g., Doyle et ul., 1979), through uptake of vesicles in vivo. The success of liposomes as a means of introducing material into cells gives striking evidence of art imitating nature in this respect (cf. Papahadjopoulos, 1978; Celis et al., 1980). However, even more direct data arc now available, indicating that the lysosomal enzyme P-glucuronidase is acquired by deficient fibroblasts from direct cell-to-cell contact with normal lyphocytes rather than by mere fusion with shed extracellular vesicles (Olsen et al., 1981). Are the foregoing indications for exchanges of lysosomal products between cells subject to regulation by well-characterized effectors? And are such transfers of direct relevance to the functions of the recipient cells'? If so, how? In the remaining sections of this article we provide some suggestions, clearly speculative and requiring rigorous testing, of the potential significance to the life of the cell of the controlled passage of critical macromolecules in vesicular form across its boundaries. First, as to regulation of such passages, a few examples may suffice: Mattson had demonstrated that ACTH elicits in cultured murine adrenocortical tumor cells striking extensions of microvillar processes between neighboring cells. These processes are crowded with lysosomes in orderly longitudinal arrays suggestive of participation of microtubules (Mattson and Kowal, 1982). It will be

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21 1

recalled that when cultured cells of murine adrenal and rat Leydig cell tumor lines were treated with ACTH or with CAMP, respectively, the steroidogenic responses were accompanied by redistribution of tubulin, as determined by indirect immunofluorescence, from membrane-bounded granules to organized microtubular form (Clark and Shay, 1981). The granules, which were also enriched in acid phosphatase, had the additional features of appropriate dimensions (0.2-0.6 pm diameter) and sensitivity to structural labilization that were in accord with their probable identity as lysosomes. The potential of organized microtubules for routing of intracellular precursor traffic during steroidogenesis is evident from this and related work (see Table XVIIIA,B). Acquisition of such potential by recompartmentation of the monomeric elements from a reservoir with lysosomal features is indeed an economical means of coupling secondary metabolic responses to an initial receptor-mediated event. However, such a mechanism taken in context with the elegant ultrastructural observations of Mattson and Kowal (1982) is also strongly suggestive of a potential means of signal transmission to that neighboring cell with which the elongated pseudopodium, elicited by progressive microtubule organization (Clark and Shay, 198I ) and further promoted by apparent loss of subplasmalemmal microfilaments (Mattson and Kowal, I982), makes intimate physical contact under hormonal control. Gap junctions formed and, in turn, dispersed under phased hormonal control may also serve to couple the metabolic responses of neighboring cells, e.g., in oocyte maturation (Anderson and Albertini, 1976; Gilula et al., 1978). Direct communication seems indicated in the promotion by peritubular cells, added to Sertoli cell culture, of androgen-binding protein secretion by the latter; conditioned medium alone did not suffice (Hutson and Stocco, 1981; Hutson, 1982), while passage of an LHRH factor from testicular Sertoli to Leydig cells in vitro has been indicated (Sharpe et al., 1981). External passage by cell-cell contact of an EGF receptor may represent a corresponding means of cellular coordination (cf. Das et al., 1981). Indeed, it is implicit in the degree of metabolic cooperation and the coordinated, occasionally sequential (cf. Korach and Lamb, 198I), responsiveness of neighboring cells that information in the form of macromolecules (cf. Meda et al., 1982) and, potentially, vesicles(?) is being exchanged. The partial coupling of the cell cycles to those of neighboring imaginal disc cells may be a further illustration of such phenomena (Adler and MacQueen, 1981) that would bear direct investigation. Cell-cell channel formation in uterine smooth muscle cells is shown to be elicited by liposome-encapsulated mRNA for gap junction protein (Dahl et al., 198 I ) . Other means of manipulation of cellular interactions, both pro and con, include application to the cultured cells of antisera to the proteins shed by mouse mammary carcinoma (Damsky et al., 1981). Increase in size and number of gap junctions between pancreatic p cells during stimulation of insulin secretion (Meda et al., 1979) has been correlated with the insulin content of the respective cells (Meda et al., 1980). These randomly

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selected illustrations serve to indicate the plasticity to a variety of challenges of the membrane barriers intervening between cells. In light of some of the above indications for developmental effects, it is not too surprising that evidence for cell-to-cell passage of vesicular components during embryonic differentiation is already available. Thus, Cunha and co-workers, who have studied extensively the role of tissue interactions in morphogenesis and cytodifferentiation of female urogenital organs, present ultrastructural evidence strongly suggestive of active exocytosis of vesicular material from stromal cells, accompanied by vesicular uptake at the epithelial cell interface, in neonatal mice, with or without estrogen treatment (Cunha and Lung, 1979). In support of the heterotypic transfer of vesicular material critical to epithelial development in the known direction of inductive stimulation (from stroma to epithelium), these workers undertook morphometric analysis of the spatial distribution of such vesicles and found a gradient of the appropriate polarity (Cunha and Lung, 1979). While the nature and source of the vesicular contents are unknown, the findings are indeed provocative and may have their counterparts in additional developmental processes, including application to the role of the androgenresponsive mesenchyme in the induction of prostatic epithelium (Lasnitzki and Mizuno, 1979; cf. also, Cunha et al., 1980). In turn, androgen sensitivity is elicited by induction of receptors to testicular hormones in mesenchyme as a result of epithelial interactions (Heuberger et al., 1982). The reciprocal interaction in the mesenchymally induced formation of androgen sensitivity of epithelium has also been identified (Cunha et at., 1980).

IV. Selected Cellular Functions Subject to Lysosomal Influence A. CELLDEATHAND SOMEANOMALIES OF INTERPRETATION In view of these relatively recent developments, and in consideration also of the profound increase in lysosomal numbers and activities during hormonally regulated tissue remodeling of the more drastic kind, as in the development of cells at expense of the destruction of others in insect metamorphosis (Lockshin and Beaulaton, 1974a,b; van Pelt-Verkuil, 1979), it is instructive to review briefly still earlier indications of profound lysosomal dominance in such developmental processes. The early observation of Hamilton and Teng (1965) on the probable lysosomal source of the Mullerian inhibitory factor that is responsible for destruction of the embryonic female generative tract, a regressive process later recognized to be under the control of fetal androgen in the male genotype, is a case in point (cf. also, Wolff, 1959). More recently, it has been shown that extracts of newborn calf testis enriched in Mullerian regression factor possessed cytotoxicity toward human ovarian cancer cells (Donahoe et ul., 1979). Like-

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wise, the destruction of embryonic epithelial mammary gland buds by the underlying mesenchyme under androgen influence (Kratochwil and Schwartz, 1976) may well have a lysosomal feature not hitherto identified. Thus, cell death under unmitigated hormonal control (cf. Schwartz and Truman, 1982; Moulton, 1982) is a phenomenon with the more familiar ring of the original “suicide-bag’’ concept of lysosomal function. There are as many unresolved questions on the precise molecular mechanisms associated with cell death (cf. Berlin et al., 1978b) as there are on those related to cell growth. The highly specialized subject of natural killer cells and their environmental regulation will not be considered here, although it is tempting to do so, in part because of the crucial role of surface recognition as the primary and discriminatory step in the initiation of a staged effector-mediated process. Moreover, in the immunologic context, there are some striking, but hitherto isolated (cf. Loor, 1981), examples of transfer of “small vesicles” at regions of deep penetration of killer pseudopodes into the target cell cytoplasm (Koren et al., 1973; Adelstein et al., 1976; cf. however, Sanderson and Glauert, 1979). Nevertheless, the biochemical mechanisms thus far identified clearly implicate lysosomal functions in the natural killer cell system (e.g., Roder et al., 1980; Hart, 1981, 1982; Om et al., 1982). Indeed, the recent demonstration of peroxidase activity in lysosomes (Bursztajn and Libby, 1981) may have a bearing on peroxidative mediation of some cidal effects (Hart, 1982; Klebanoff et al., 1982). Modulation of the latter may likewise be a function of relative availability of lysosomal superoxide dismutase (cf. Geller and Winge, 1982). What will be emphasized, instead, are some observations, interpreted in the first flush of enthusiasm for hormonal control at the transcriptional level, which led to the premature conclusion that RNA and protein “synthesis” were obligatory antecedents to cell death. It is instructive to review these ideas in the clear light of historical precedent. In the mid-l940s, White and Dougherty demonstrated a striking involution of lymphoid tissue, together with profound depletion of lymphocytes in the circulation, in rodents treated either with ACTH or with milligram doses of glucocorticoids (reviewed in White, 1949, 1950). Concomitantly, there was a rise in plasma amino acid and elevation in urea nitrogen, suggestive of accentuated catabolism of the proteins so clearly mobilized from the lymphocyte germinal centers. Histologic examination of the latter revealed that the lymphocytes were in all stages of cellular breakdown-from “foam cells” to naked nuclei. Indeed, the lymphoid tissue hypertrophy in adrenalectomized animals was viewed as withdrawal of the tonic mobilizing activity of endogenous adrenocortical function. Somewhat later, Roberts (1953) demonstrated that the effects of adrenocortical hormones on nitrogen mobilization were tissue-specific and biphasic, with inversion of the catabolic dominance at low doses. These latter findings helped to reconcile the earlier data with the puzzling requirement for “permissive” levels

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CLARA M. SZEGO AND RICHARD J . PIETRAS

of adrenocortical hormones in the promotion of growth in young, and in niaintenance of nitrogen equilibrium in mature animals. However, such relatively “gross” observations at the whole animal level were rapidly eclipsed in the wave of enthusiasm for analyses of adrenocortical steroid hormone action at the genomic level. Such was the impact of the operon, a concept that was revolutionizing microbiology. Accordingly, and generally prematurely (see Section II,A), its implications were widely accepted as directly applicable to eukaryotic cells as well. Unfortunately, however, the experimental base was flawed, for highly toxic inhibitors were utilized to “block specific DNA-dependent KNA synthesis” in experiments to determine whether effectors could elicit their costomary metabolic influences either in isolated cells (in which severe membrane damage and death ensued) or in whole animals (ditto). To the astonishment of many, application of the inhibitors themselves, in the absence of putative effectors, elicited, per se, “paradoxical induction” of the very proteins whose synthesis was subject to agonal control. It is by no means outside the scope of this review to consider the evidence for lysosomal participation not only in the programmed consequences of surface receptor interactions with specific effectors, but also in those cases of “paradoxical” induction of given proteins that have been generally viewed as anomalous responses to a variety of relatively toxic substances (Table XXIII). In the case of the latter phenomena, some intriguingly discordant explanations have thus far been put forward (Tomkins et al., 1972; Palmiter and Schimke, 1973; Kenney et al., 1973); none of these has fully explained the observations. The purpose of presentation of the assorted data in Table XXIIl is not to raise a straw man. Indeed, the gross membrane damage and generalized toxicity elicited by these several and many other “specific” inhibitors of protein and nucleic acid “synthesis” have long been recognized [e.g., Waksman et al., 1941; Robinson and Waksman, 1942; Hackmann, 1954; Philips et al., 1960; Gale, 1963; Harris and Sabath, 1964; Revel et al., 1964; Korn et al., 1965; Lippe and Szego, 1965; Szego and Lippe, 1965; Greif et a/., 1965; Laszlo et al., 1966; Soeiro and Amos, 1966; Spaziani and Suddick, 1967; Weinstock, 1970; Miles, 1970; Verbin e t a / ., 1971; Schwartz, 1973 (cf., however, Jones ef al.. 1974); Pater and Mak, 1974; Meller el al., 1974; Sturgess et ul., 1975; Mitranic et al., 1976; and Kellokumpu-Lehtinen and Tuohimaa, 19781. Moreover, the secondary effects of antibiotics upon metabolic functions, including those related to plasmalemmal, Golgi, EK, and mitochondria1 activities, may be attributable to relatively gross primary effects upon lysosomal organelles, accompanied by massive, but sublethal, “spilling” of hydrolase content. It has long been recognized that lysosomes selectively accumulate a wide range of exogenous substances, both organic and inorganic, soluble as well as particulate (cf. Allison, 1968). In keeping with this property, there is found among cultured rat fibroblasts an extraordinary degree of uptake and accumulation of aminoglycoside (Tulkens and Trouet, 1978) and

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