Lack of tropomyosin correlates with the absence of stress fibers in transformed rat kidney cells

Leonardi, Craig L.; Warren, Robert H.; Rubin, Robert W.

doi:10.1016/0167-4889(82)90007-6

Cited by 77 publications

(34 citation statements)

References 30 publications

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“…Early studies have found that cell transformation by oncogenic Ras and Src leads to down-regulation of tropomyosins and disruption of actin stress fiber filaments (Leonardi et al, 1982;Hendricks and Weintraub, 1984). Subsequently, it has been shown that ectopic expression of tropomyosins in Ras-transformed fibroblasts restores stress fibers and significantly reduces cell motility and cell growth (Takenaga and Masuda, 1994;Braverman et al, 1996;Gimona et al, 1996;Janssen and Mier, 1997).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

Bakin

Safina

Rinehart

et al. 2004

MBoC

135

208

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We have investigated transforming growth factor beta (TGF-␤)-mediated induction of actin stress fibers in normal and metastatic epithelial cells. We found that stress fiber formation requires de novo protein synthesis, p38Mapk and Smad signaling. We show that TGF-␤ via Smad and p38Mapk up-regulates expression of actin-binding proteins including high-molecular-weight tropomyosins, ␣-actinin and calponin h2. We demonstrate that, among these proteins, tropomyosins are both necessary and sufficient for TGF-␤ induction of stress fibers. Silencing of tropomyosins with short interfering RNAs (siRNAs) blocks stress fiber assembly, whereas ectopic expression of tropomyosins results in stress fibers. Ectopic-expression and siRNA experiments show that Smads mediate induction of tropomyosins and stress fibers. Interestingly, TGF-␤ induction of stress fibers was not accompanied by changes in the levels of cofilin phosphorylation. TGF-␤ induction of tropomyosins and stress fibers are significantly inhibited by Ras-ERK signaling in metastatic breast cancer cells. Inhibition of the Ras-ERK pathway restores TGF-␤ induction of tropomyosins and stress fibers and thereby reduces cell motility. These results suggest that induction of tropomyosins and stress fibers play an essential role in TGF-␤ control of cell motility, and the loss of this TGF-␤ response is a critical step in the acquisition of metastatic phenotype by tumor cells. INTRODUCTIONThere is solid evidence that the transforming growth factor beta (TGF-␤) signaling pathway is a major cellular growth inhibitory and proapoptotic pathway in epithelial, endothelial, hematopoeitic, and other cell types (Roberts and Wakefield, 2003). However, clinical and experimental studies indicate that metastatic cancers of the breast and other tissues express elevated levels of TGF-␤ that appears to support the metastatic behavior of the tumor cells (Saito et al., 2000;Derynck et al., 2001). This apparent paradox has been associated with a progressive decline in the antitumorigenic function and a gain of protumorigenic activities of TGF-␤, including induction of epithelial to mesenchymal transition (EMT) and tumor cell migration and invasion (Derynck et al., 2001;Wakefield and Roberts, 2002). Oncogenic Ras, Src, and ErbB2 as well as alterations in TGF-␤ signaling mediated by Smads, mitogen-activated protein kinases (Mapks), Rho kinases, and Akt/PKB are thought to contribute to the metastatic phenotype (Derynck and Zhang, 2003;Roberts and Wakefield, 2003).The actin cytoskeleton plays a central role in the regulation of cellular processes linked to metastasis including cell proliferation, apoptosis, anchorage-independent cell growth, and cell migration and invasion (Pawlak and Helfman, 2001;Jaffe and Hall, 2002). TGF-␤ induces a rapid reorganization of the actin cytoskeleton, leading to membrane ruffling at the cell edges in both nontumorigenic and tumorigenic epithelial cells, whereas a prolonged incubation with TGF-␤ results in the formation of stress fibers (Bakin et al., 2002;Edlund et a...

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Section: Discussionmentioning

confidence: 99%

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

Bakin

Safina

Rinehart

et al. 2004

MBoC

135

208

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“…Changes in the expression of a number of micro®lament-associated proteins during neoplastic transformation have been well documented (Button et al, 1995;Jammey and Chaponnier, 1995). For example, the expression of gelsolin (Vandekerckhove et al, 1990), vinculin (FernaÂ ndez et al, 1992), a-actinin (GluÈ ck et al, 1993) and tropomyosins (Leonardi et al, 1982;Cooper et al, 1985;Lin et al, 1985;Matsumura et al, 1983), which bind to and/or modulate the polymerization status of actin, is reported to be down regulated as the cells acquire malignant phenotype.…”

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confidence: 99%

Suppression of src-induced transformed phenotype by expression of tropomyosin-1

et al. 1999

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Suppression of high M r tropomyosins (TMs) is a common feature of transformed cells. Previous work from this laboratory has demonstrated that the isoform 1 of TM, TM1, acts as an anti-oncogene in rastransformed murine ®broblasts. In this study, we have investigated whether TM1 is a ras-speci®c suppressor, or a general suppressor protein of the cellular transformation. V-src transformed ®broblasts, which express decreased TM1, were transduced with a full-length cDNA to overexpress TM1. Both the control and the transduced cells expressed v-src kinase at comparable levels. TM1 expressing (src-T1) cells grew at a lower rate in monolayer, exhibited well spread,¯at morphology than the control cells. Enhanced expression of TM1 resulted in improved micro®lamental architecture. More signi®cantly, src-T1 cells completely failed to grow under anchorage independent conditions. These data demonstrate that TM1 is as an anti-oncogene of functionally diverse oncogenes, and it is a class II tumor suppressor protein.

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“…Finally, the decrease in TM synthesis is temperature sensitive in cells infected with a ts-RSV transformation mutant (M. Hendricks, unpublished data). More recently, others have also reported reduced levels of TM in various other transformed cells (5,29,35). All of these studies suggest that TM plays a major role in the organization of microfilaments into bundles and consequently in the phenotypic changes that occur as a result of oncogenic transformation.…”

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Multiple tropomyosin polypeptides in chicken embryo fibroblasts: differential repression of transcription by Rous sarcoma virus transformation.

Hendricks¹,

Weintraub²

1984

Mol. Cell. Biol.

130

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We have found that cytoskeletal extracts of cultured chicken embryo fibroblasts contain at least seven distinct polypeptides (two major and five minor) which cross-react with antiserum to chicken smooth muscle tropomyosin. These polypeptides range in apparent molecular weight from 31,000 to 47,000, and each is encoded by mRNAs which specifically hybridize to cloned muscle tropomyosin cDNAs. These nonmuscle tropomyosin species and their respective mRNAs are electrophoretically distinct from those of chicken skeletal muscle and appear by genomic DNA blotting to comprise a part of a multigene tropomyosin family. In Rous sarcoma virus-transformed chicken embryo fibroblasts, synthesis of the tropomyosins is differentially repressed such that the synthesis of the major species (cp35 and cp33, cytoskeletal proteins of molecular weight 35,000 and 33,000, respectively) and three minor species is drastically reduced, whereas the synthesis of two of the minor species (cp32 and cp3l) remains essentially unchanged. Analysis of cellular mRNA and runoff nuclear transcription experiments indicate that the repression of tropomyosin synthesis by Rous sarcoma virus transformation occurs at the level of transcription. This repression of tropomyosin synthesis is partially mimicked in normal chicken embryo fibroblasts during incubation in high-NaCI medium, a condition in which chicken embryo fibroblasts acquire many characteristics of transformed cells.Tropomyosin (TM) is a protein which has been best studied in skeletal muscle, where it is associated with actin in thin filaments and, together with the troponin complex, is responsible for mediating the effect of calcium on the contraction-generating interaction of actin and myosin (11,24). In nonmuscle cells (which do not contain troponin), TM is associated with actin in microfilaments (28,36,50) and, although the function of TM in these filaments is not known, there is evidence suggesting that one function resides in its ability to stabilize F-actin polymers (3,13). TMs from a variety of nonmuscle sources have been characterized (9,10,14,15,17), and a distinctive feature of these nonmuscle species has been their apparent molecular weight of 30,000, significantly less than that of skeletal muscle TM, which has a molecular weight range of 34,000 to 36,000. However, two forms of nonmuscle TM with significantly larger apparent molecular weights of 35,000 and 33,000 were identified in the cytoskeleton of cultured chicken embryo fibroblasts (25). More recently, multiple forms of TM having a broad range of molecular weights have been identified in the cytoskeleton of human fibroblasts (44) and in microfilaments of a variety of other cultured mammalian cells (35,36).It is commonly believed that microfilaments play a major role in cell motility and cell shape changes (7,18,27). A general feature of oncogenic transformation is the morphological alteration of the cell (for reviews, see references 23 and 45). Correlated with this change in cell morphology is a dramatic change in the organizatio...

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Lack of tropomyosin correlates with the absence of stress fibers in transformed rat kidney cells

Cited by 77 publications

References 30 publications

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

A Critical Role of Tropomyosins in TGF-β Regulation of the Actin Cytoskeleton and Cell Motility in Epithelial Cells

Suppression of src-induced transformed phenotype by expression of tropomyosin-1

Multiple tropomyosin polypeptides in chicken embryo fibroblasts: differential repression of transcription by Rous sarcoma virus transformation.

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