CYTOSKELETAL PROTEINS IN ONCOGENIC TRANSFORMATION AND HUMAN NEOPLASIA

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We are examining the relationship between neoplastic transformation and biochemical derangements of expression or utilization of tropomyosins (TMs). In NIH/3T3 fibroblasts transformed by a number of related and unrelated retroviral oncogenes, expression of the transformed phenotype was reproducibly correlated with suppression of synthesis of two specific TM isoforms ("muscle type"). Of all the proteins detectable on two-dimensional gel electrophoresis of whole-cell proteins, only the TMs behaved in this way. Treatment of rat fibroblasts with tumor growth factor-alpha (TGF-alpha), in addition to inducing the transformed phenotype, specifically suppressed synthesis of muscle-type TMs and inhibited their utilization in the cytoskeleton, strengthening the connection between suppression of TM and expression of the transformed phenotype and adding support at the biochemical level for an autocrine pathway in oncogene action. The findings point out the close biochemical relationship between epidermal growth factor (EGF) receptor activation and microfilament organization. Tropomyosin expression in relation to oncogene expression and neoplasia is being studied in murine and human epithelial cell systems. In mouse mammary epithelial cells transformed by the Ha-ras oncogene, the ratio of TM to actin accumulating in the cytoskeleton was reduced, indicating the production of microfilaments deficient in TM. The TM isoforms expressed by normal diploid human mammary epithelial cells have been compared with the pattern expressed by breast carcinoma cell lines. Defects in expression of particular TM isoforms occurred in all of the breast carcinoma cell lines studied, suggesting a possible role of deranged TM expression in human neoplasia.