THE REGULATORY MECHANISM OF ONCOGENE EXPRESSION

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In spite of the relatively large body of information concerning the molecular structure of retrovirus oncogenes and their specific protein products, little is known about the mechanisms by which they transform cells. Moreover, proto-oncogenes, the cellular counterpart of retroviral oncogenes, have been found in normal cells but their expression is low and the mechanism for this low expression is not known. It is conceivable that substances that increase tumor development by apparently increasing cellular proliferation do so by altering the quantitative or temporal expression of cellular oncogenes. Understanding the cellular mechanisms governing the expression of both viral and cellular oncogenes would therefore provide an insight into the mechanism of neoplastic cell growth and tumor development. Occasionally, tumor cells differentiate spontaneously and then regress completely. It has been suggested that cAMP may be linked with the morphological differentiation of neoplastic cells since treatment of some tumor cells with dibutyryl cAMP, prostaglandin E1 and inhibitors of cAMP-phosphodiesterase induces irreversible morphological differentiation. That this differentiation may be a reversion of malignancy is supported by the observation that no tumor is produced when these treated cells are inoculated into animals. To investigate factors that affect phenotypic reversion of transformed cells, we have chosen a cell line 433 of NIH 3T3 cells containing the transforming ras gene of Ha-MuSV flanked by LTR of MMTV; the expression of ras gene in 433 cells is therefore controlled by mouse mammary tumor virus promoter (MMTV-LTR) which is under control of glucocorticoid. Thus, the phenotypically normal 433 cells become transformed and produce the ras gene product, p21, only upon addition of glucocorticoid. We also used clone 13-3B-4 of NIH 3T3 cells, the Ha-MuSV DNA transfectant, whose epxression of v-rasH gene is not under control of glucocorticoid. The goal of this study is to investigate the effect of intracellular regulatory factors, such as, cyclic nucleotides, hormones, and growth factors on the MMTV-LTR, and MoLV-LTR regulated expression of ras gene.