Mutation Research, 256 (1991) 139-148

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© 1991 Elsevier Science Publishers B.V. All rights reserved 0921-8734/91/$03.50

MUTAGI 00157

Actin cytoskeletal network in aging and cancer K. Murali Krishna Rao and Harvey Jay Cohen Geriatric Research, Education and Clinical Center, Department of Veterans Affairs Medical Center; Centerfor the Study of Aging and Human Deeelopment, Duke University Medical Center, Durham, NC 27705 (U.S.A.)

(Accepted 3 June 1991)

Keywords: Cell proliferation; Extracellular matrix proteins; Integrins; Proteoglycans;Second messengers; Enzyme regulation

Summary The cytoskeleton is being recognized as an important modulator of metabolic functions of the cell. The actin cytoskeletal network, in particular, is involved in events regulating cell proliferation and differentiation. The state of actin in a variety of cell types is regulated by signals arising from the cell surface through a wide spectrum of interactions. In this review, we explore the role of actin cytoskeletal network in a series of events which are known to influence cell proliferation and differentiation. These include interaction of actin network with extracellular matrix proteins, cell surface membranes, second messengers, cytoplasmic enzymes and the nucleus. Because of the involvement of the actin network in such diverse interactions, we propose that alterations in the actin cytoskeletal function may be an important aspect of generalized decrease in cellular functions associated with aging. Preliminary data indicate that alterations in the cytoskeletal network do occur in cells obtained from older individuals. Alterations in actin state are also reported during malignant transformation of cells in culture, and in naturally occurring tumors. Taken together, the existing data seem to suggest that changes in the actin cytoskeletal network may be a part of the aging process as well as malignant transformation. Therefore, the study of the actin cytoskeletal network and its regulation has the potential to yield important information regarding cellular senescence and neoplastic transformation.

The cytoskeleton is being recognized as an important modulator of metabolic functions of the cell. We have previously put forward the concept that changes in the function of cytoskeletal elements may have a role in the aging process (Rao and Cohen, 1990); in this review we would like to focus on the actin cytoskeletal network. We will provide evidence, from the literature,

Correspondence: K. Murali Krishna Rao, M.D., Box 182 A, V.A. Medical Center, Durham, NC 27705 (U.S.A.).

that supports a role for the actin cytoskeletal network in a variety of cellular functions and relate these changes to the aging process, focusing on those events which are associated with cell proliferation and neoplastic transformation. Age-related changes in cell proliferation can be either a decrease in the replicative capacity, as classically observed with fibroblasts (Hayflick, 1965), or uninhibited proliferation as seen with malignant transformation. The susceptibility to malignant transformation with age is documented by the increased incidence of malignant disease

140 in older individuals (Crawford and Cohen, 1987). Together, the aberrations in cell proliferation can be considered 'dysregulation' of cell growth. In this review, we will endeavor to show that the actin cytoskeletal network may play a part in both these processes.

Actin cytoskeletal network Actin is one of the most abundant proteins in the cell, constituting as much as 10% of the total cellular protein in certain cell types (Weeds, 1982). It exists in monomeric (G-actin) and polymeric (F-actin) form. F-actin is the major constituent of the microfilaments; morphologically these structures are described as stress fibers. Stress fibers are noted in a variety of cell types, being particularly prominent in spread-out cultured cells (Fernandez et al., 1990), and in some intact tissues such as endothelial cells lining the vasculature (Guyton et al., 1989). The morphological features of the actin cytoskeletal networks have been well described in macrophages (Hartwig and Shevlin, 1986; Hartwig and Yin, 1988), neutrophils (Cassimeris et al., 1990), platelets (Hartwig et al., 1989), fibroblasts (Svitkina et al., 1986) and neurons (Luduena and Wessells, 1973; Spooner and Holladay, 1981) to mention a few examples. The actin filaments are particularly prominent in lamellipodia, where rapid turnover of F-actin seems to occur in cell types as diverse as neutrophils (Cassimeris et al., 1990), fibroblasts (Svitkina et al., 1986) and neurons (Bray and White, 1988). It has been proposed that cells might possess several different types of actin filaments that differ in their spatial distributions and relative stabilities (Cassimeris et al., 1990). Part of these differences may be attributed to their association with different actin binding proteins (Drenckhahn et al., 1991). A large number of actin binding proteins (Stossel et al., 1985; Weeds, 1982) have been described and their number continues to increase (Yang et al., 1990; Ankenbauer et al., 1989; Safer et al., 1990). Alterations in function or expression of these molecules may have profound effect on the actin state in cells. There is evidence that some of the actin binding proteins such as adducin (Bennett et al., 1988) and vinculin (Ruhnau and Wegner, 1988) bind

directly to actin filaments and modulate their binding to other proteins. In addition, the actin binding protein profilin has been shown to regulate phospholipase C (Goldschmidt-Clermont et al., 1991). Thus, actin binding proteins by reversibly associating with the cytoskeleton may play a mediator role in modulating second messenger activity; and second messengers, in turn, might regulate actin organization by interacting with actin binding proteins (Lassing and Lindberg, 1988).

Regulation of the actin cytoskeletal network Actin in ceils exists in a dynamic state, with rapid interconversion between G-and F-actin. Activation of the cells with a variety of agents causes a rapid increase in the F-actin content in a number of cell types. Stimulus-induced actin polymerization has been demonstrated in neutrophils (Fechheimer and Zigmond, 1983; Howard and Meyer, 1984; Rao and Varani, 1982), lymphocytes (Laub et al., 1981; Rao, 1984; Phatak et al., 1988), platelets (Pribluda et al., 1981; Fox and Phillips, 1981), neurons (Bernstein and Bamburg, 1987; Bahler and Greengard, 1987), hepatocytes (Rao et al., 1985) to mention a few examples. The stimulants represent a wide variety of substances, including bacterial products such as chemotactic peptides (Fechheimer and Zigmond, 1983; Howard and Meyer, 1984; Rao and Varani, 1982), tumor promoters such as phorbol esters (Rao, 1985; Phatak et al., 1988), hormones (Rao et al., 1985; Siegrist-Kaiser et al., 1990) and a variety of other substances (Birrell et al., 1990; Omann et al., 1987). These observations indicate that multiple pathways might exist for regulating actin state in cells. Some of the biochemical events which have been implicated in the regulation of actin state include changes in phosphatidylinositol turnover, activation of protein kinase C and production of arachidonic acid metabolites, etc. We will allude to these signals as they relate to agerelated changes in the dysregulation of cell proliferation. The role of the actin cytoskeletal network in cell proliferation The role of the actin cytoskeletal network in maintaining cell shape and causing cell move-

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ment is well documented. However, in addition to this important function, it is becoming clear that actin filaments may play a major role in regulating the metabolic activity of cells (Masters, 1981; Poglazov, 1983). In this review, we will focus on the role of actin-based structures in modulating cell proliferation and differentiation. Most of the evidence for the role of actin filaments in cell proliferation is based on experiments using cytochalasins in cell cultures. Cytochalasins inhibit cell proliferation in a variety of cell types such as GC-7 (African green monkey kidney cell line) (Takasuka et al., 1987), lymphocytes (Freed et al., 1989; Medrano et al., 1974; Greene et al., 1976), and fibroblasts (Rebillard et al., 1987). The exact mechanism of action, however, is not known. The role of actin in cell differentiation, again, is based on the effects of cytochalasins on cultured cells. Cytochalasins have been shown to block the morphogenetic cascade in testicular cells by blocking direct cell contact (Tung and Fritz, 1987). Similarly, gonadotropin-induced differentiation of granulosa cells seems to require actin cytoskeletal integrity (Ben-Ze'ev et al., 1987). Terminal differentiation of keratinocytes also involves reorganization of the actin cytoskeleton (Lewis et al., 1987). In certain instances, for example in human thyroid cancer cells, actin architecture may be used as a predictor of differentiation (Demeure et al., 1990). The factors that induce cells to undergo proliferation and differentiation are numerous and the molecular events involved encompass the entire gamut of cell and molecular biology. We will explore the role of the actin cytoskeleton in the regulation of cell proliferation and differentiation by gathering the evidence for the involvement of the actin cytoskeletal network in a series of events which are known to influence cell proliferation and differentiation. These can be categorized into (1) events outside the cell, (2) events at the cell surface, (3) changes in the second messenger levels, (4) cytoplasmic events, and (5) nuclear events. We will ascertain the role of the cytoskeleton in each of these events and relate it to the changes associated with aging and neoplastic transformation.

The role of the actin network in cell/matrix interactions A prominent feature of multicellular organisms is the frequent and ordered interactions of the cells with each other and the interconnecting extracellular matrix at structures called focal contacts. The structural precursor of the focal contact has been shown to be an F-actin-rich rib-like fiber in fibroblasts (Izzard, 1988). These contact sites are also called adhesion plaques (Burridge et al., 1987, 1988) or adherence junctions (Geiger, 1989). Adhesion plaques are the sites of attachment of the stress fibers to the plasma membrane and are also the sites that attach to the extraceIlular matrix. The focal contacts are the regions of communication between the external environment and the cells. Several potential regulatory enzymes, many of them tyrosine kinases (some, products of viral oncogenes) are located at the cytoplasmic face of the adhesion plaques. The interaction between the cell surface and the matrix proteins or other cells is mediated by a group of heterodimeric molecules, collectively known as integrins (Albelda and Buck, 1990; Hynes, 1987; Ruoslahti and Pierschbacher, 1987). They play an important role in development, inflammation, wound healing, coagulation and tumor metastasis (Albelda and Buck, 1990). Integrins appear to modulate these functions through their interaction with the cytoskeleton (Burridge and Fath, 1989). The interactions between the integrins and the cytoskeleton seem to take place at the adhesion plaques. Quiescent fibroblasts, when induced to grow, express actin, fibronectin and fibronectin receptors in a coordinate fashion, suggesting close interrelationships between the actin network and the cell matrix proteins (Ryseck et al., 1989). Another set of important proteins which interact with extracellular matrix molecules are proteoglycans. The interaction of proteoglycans with the extracellular matrix proteins is known to promote organization of actin filaments (Saunders and Bernfield, 1988; LeBaron et al., 1988; Izzard et al., 1986). Further, it is suggested that proteoglycans may play a role in cell proliferation (Ruoslahti, 1989). In view of the important role actin organization seems to play in cell prolifera-

142 tion, it remains to be determined whether the changes induced by proteoglycans in actin reorganization have any role in cell proliferation. There is also evidence to suggest that the actin cytoskeleton may be involved in the regulation of proteoglycan synthesis (Newman and Watt, 1988). Differentiated cells tend to produce more proteoglycan and tend to possess less proliferative potential; a phenomenon well documented in chondrocytes (Newman and Watt, 1988; Chacko et al., 1969). The differentiation process is associated with profound morphological changes. Thus, it seems likely that the cytoskeletal reorganization and proteoglycan synthesis may have a mutual regulatory role. Interactions between the actin network and cell surface membrane The actin cytoskeleton interacts closely with the plasma membrane (Carraway and Carraway, 1989). Apart from its interaction with matrix proteins and other cells through adhesion plaques, the actin cytoskeleton also interacts with various cell surface receptors. Such interactions are well documemted in platelets and leukocytes (Crawford et al., 1989). As discussed above, stimulation of cells with a variety of agents can induce actin polymerization and cellular activation. A number of events which take place at the cell surface membrane, such as expression of surface molecules (Dainiak et al., 1988), capping and shedding (de Petris, 1974; Yahara and Edelman, 1991), require an intact actin network. Interrelationships between second messengers and the actin network Cell proliferation is accompanied by alterations in cellular second messengers. Several observations suggest that there is an intimate relationship between the second messenger generation and actin reorganization; conversely, integrity of the actin cytoskeletal network seems to be required for the generation of second messengers. For example, a 'fall' in cAMP levels appears necessary for cell spreading and actin reorganization in TNF-induced neutrophils, at the same time it appears that cytoskeletal integrity is required for the fall in cAMP (Nathan and Sanchez,

1990). This type of relationship may be explained on the basis of different pools of the actin cytoskeletal network coming into play in these two interactions. Other second messengers implicated in the regulation of the actin network include products of phosphatidylinositol metabolism; in particular phosphatidylinositol bisphosphate (PII~2) has been shown to interact with profilin, leading to the suggestion that this interaction might be involved in actin reorganization (Lassing and Lindberg, 1988). A role for protein kinase C in actin reorganization seems likely because of the ability of the phorbol esters to induce actin polymerization (Rao, 1985; Phatak et al., 1988; Sastrodihardjo et al., 1987). In fibroblasts, the actin network is regulated by cAMP-dependent kinase, myosin light chain kinase and protein phosphatase 1 (Fernandez et al., 1990). Our recent work suggests that similar control mechanisms might exist in neutrophils (Padmanabhan et al., 1991). Treatment of cells with cytochalasins has also been shown to influence free intracelluar calcium levels (Treves et al., 1987; Backer et al., 1987) and phosphoinositide metabolism (Treves et al., 1987; van Haelst-Pisani et al., 1989), again suggesting that the actin network is regulated by second messengers, and it in turn can influence the production of second messengers. Thus, these interactions may be part of a complex network of mutual regulatory processes which can fine-tune the cellular responses to stimuli and maintain homeostasis.

The role of actin in regulating cytoplasmic enzymes As described above a variety of stimuli induce reorganization of the actin cytoskeletal network in cells. The consequence of this reorganization seems to be an alteration in the metabolic activity of the cell. The alteration in the metabolic activity seems to be caused by the association of a variety of enzymes with the actin cytoskeletal network. A number of glycolytic enzymes seem to associate with F-actin (Masters, 1981; Chen and Masters, 1989; Shearwin et al., 1989) and undergo a change in their activity. In other cases, the biological half life of the enzyme is altered by association with the cytoskeleton, as seen with

143

type I1 iodothyronine 5'-deiodinase (Leonard et al., 1990; Farwell et al., 1990). Formation of ll(/3)-hydroxysteroids seem to require the integrity of the microfilament network suggesting that enzymes involved in steroid biosynthesis may be influenced by the actin cytoskeleton (Feuilloley et al., 1987). It is likely that more such interactions will become evident in the future and that the actin cytoskeleton may assume a prominent role in the age-related changes in hormone synthesis, secretion and regulation (Sonntag, 1987). The role of actin in the nucleus Actin is a constituent of the nuclear compartment (Capco et al., 1982; Valkov et al., 1989; Nakayasu and Ueda, 1983), and the nuclear matrix forms an interlocking network with the cytomatrix (Pienta et al., 1989). The actin in the nuclear matrix is found in association with certain actin binding proteins (Nishida et at., 1987), whose activity in turn might regulate its interaction with DNA. Experimental evidence suggests that actin might be involved in processes such as chromosome condensation (Rungger et al., 1979), and RNA transcription (Egly et al., 1984; Scheer et al., 1984). Interestingly, complexing of actin and other proteins with DNA has been implicated as an event associated with carcinogenesis (Miller et al., 1991). The role of the actin cytoskeleton in aging

In view of the widespread presence of actin cytoskeletal structures in various tissues, and the major role they play in maintaining and regulating important physiological functions, it is reasonable to assume that any changes in the structure and function of the actin network would be reflected in a generalized change in the physiological function of the organism. Therefore, we proposed that alterations in the cytoskeleton may be an important aspect of the aging process (Rao and Cohen, 1990). In this section we will summarize some of the age-related studies which emphasize alterations in the actin cytoskeletal network. In lymphocytes, there have been some attempts to study actin cytoskeletal organization in relation to age. In Fischer F344 rats, an age-re-

lated decline in F-actin content was noted in splenic T lymphocytes (Cheung et al., 1987). In contrast, in mice the basal level of F-actin was found to be increased in splenic lymphocytes (Brock et al., 1990). Consistent with the data in mice we found that the basal F-actin in human peripheral blood lymphocytes was increased in older individuals (Rao et al., 1991). The increased F-actin content might explain the decreased filterability of mononuclear cells from elderly individuals (Ciufetti et al., 1989), and the changes in blood rheology noted during aging (Dintenfass, 1989). In contrast to the changes in the basal F-actin content in lymphocytes, the basal F-actin levels in neutrophils, studied in the same donors simultaneously, were not increased (Rao et al., 1991). This might reflect the half lives of these cells in the circulation, neutrophils having half lives of a few hours, whereas some lymphocytes may circulate for several years. Several observations provide evidence for agerelated alterations in signal transduction mechanisms. In neutrophits, the stimulus-induced actin polymerization was significantly lower in older individuals (Rao et al., 1991). This suggests that there might be related abnormalities in the signal transduction mechanisms. In T cells an age-related defect in the expression of early activation molecules has been noted (Ernst et al., 1989). They also showed a defect in the transcription of the c-rnyc gene (Gamble et al., 1990). Since actin is involved in both the expression of cell surface molecules (Dainiak et al., 1988), and nuclear transcription (Scheer et al., 1984; Egly et al., 1984), the age-related alterations in the actin cytoskeleton, which are beginning to be recognized, may be important in these changes. The consequences of these early defects may, in turn, be responsible for impaired T cell proliferation (Staiano-Coico et al., 1984) and other aspects of immunosenescence (Thoman and Weigle, 1989). In addition to changes in blood elements, agerelated changes in the actin cytoskeletal network have been reported in thyroid follicular cells (Kurihara et al., 1990), mouse lens epithelium (Liou and Rafferty, 1988) and arterial endothelial cells (Yost and Herman, 1988). Thus, changes in the actin cytoskeletal network that occur with age appear to be generalized in nature.

44

(he role of the cytoskeleton in neoplasia The increased incidence of neoplasia with age s well documented (Crawford and Cohen, 1987). ;ome of the hallmarks of cell transformation are oss of contact inhibition of growth, loss of an'.horage dependence, de-differentiation, and a lecrease in fibronectin expression, functions vhich are closely associated with adhesion ~laques. It has been shown that viral transformaion brings about changes in focal contacts (Buridge and Fath, 1989), thus perhaps contributing o neoplastic transformation. Changes in adheion plaques are associated with profound change n the cytoskeletal organization of the cell. Inter'.stingly, disruption of the actin cytoskeleton has leen shown to be an early effect of infection with ~denovirus (Jackson and Bellett, 1989). This is ~ccompanied by an increased number of actin linding sites on plasma membranes of virusransformed fibroblasts (Koffer and Edgar, 1989). 'rofound changes in the actin cytoskeleton have ~een described in several cell types infected with 'iruses (Bedows et al., 1983; Holme et al., 1986). Actin changes in cells have been suggested as ~possible mechanism for malignant tumor formaion (Holme, 1990; Ben-Ze'ev, 1985). Several tunor promoters are known to induce actin reorgatization in a variety of cell types (Keller et al., 989; Rao, 1985; Birrell et al., 1990; Sastroditardjo et al., 1987; Sobue et al., 1988), and :hanges in actin organization have been observed n many transformed cell lines (Ben-Ze'ev, 1986; Vang and Goldberg, 1976; Pollack et al., 1975; ~.offer et al., 1985). Actin cytoskeletal abnormaliies have also been shown in cultured skin fibro~lasts of patients with familial polyposis of the olon and rectum (Kopelovich et al., 1980). Viral nfections profoundly alter the actin cytoskeletal ~rchitecture (Jackson and Bellett, 1989). The cyoskeleton and the nuclear matrix are believed to ~lay an important role in virus replication Ciampor, 1988), thus the actin cytoskeleton eems to have a role in malignant transformation nduced by viruses. The edges of tumors are rich n actin structures, suggesting that the invasivetess of the tumor cells may be a function of these tructures (Gabbiani and Kocher, 1983). In fact, a B16 melanoma cell lines, the lines with high

metastatic capacity seem to have more F-actin (Holme et al., 1987). Such changes seem to be involved in benign to malignant tumor transformation and metastatic potential (Friedman et al., 1984; Raz and Geiger, 1982). Several products of oncogenes seem to have an influence on actin architecture. Transformation of fibroblasts with src oncogene, which codes for the production of the protein known as pp60, causes profound changes in the actin cytoskeleton (Felice et al., 1990, Holme et al., 1986). Disordered metabolism of microfilament proteins has also been demonstrated in mouse mammary cells expressing the Ha-ras oncogene (Bhattacharya et al., 1988). The gene product of the oncogene v-fgr is shown to be a hybrid protein containing a portion of actin and a tyrosine specific protein kinase (Naharro et al., 1984). Taken together, the existing data seem to suggest that changes in the actin cytoskeletal network may be part of the aging process as well as malignant transformation. It remains to be seen if age-related changes in the actin cytoskeleton in any way contribute to the increased incidence of cancer with age. The importance of the role of the actin cytoskeleton in the regulation of cell function and proliferation has been recognized only in the last decade. Now, several sophisticated techniques have become available to study the changes in actin state. There is still much to be learned regarding the role of actin binding proteins already discovered; and more actin binding proteins are being defined each day. In our view, the study of the actin cytoskeletal network has the potential to yield important information regarding cellular senescence and neoplastic transformation.

Acknowledgement This work was supported by funds from Department of Veterans Affairs Medical Research Program.

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Actin cytoskeletal network in aging and cancer.

The cytoskeleton is being recognized as an important modulator of metabolic functions of the cell. The actin cytoskeletal network, in particular, is i...
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