Mammalian cell proliferation is regulated by polypeptide growth factors. Accumulating evidence indicates that an important component of growth factor actions is the activation of a complex genetic program, which mediates the growth response. How growth factors and other mitogens activate this genetic program has thus emerged as a crucial link in the mechanisms controlling cell proliferation and tumorgenesis. Quiescent mouse fibroblasts can be stimulated to re-enter the cell cycle at the G1 phase by the administration of serum or purified growth factors. The interaction of growth factors with their cell surface receptors result in a signal transmitted to the nucleus, where transcriptional activation of a set of """"""""immediate-early"""""""" genes rapidly occurs. Among the genes activated in this manner are the proto-oncogenes c-fos, c-myc, and c-jun. These findings underscore the importance of these immediate-early genes. A set of 10 previously unknown immediate-early genes has been identified. These genes are regulated by serum or purified platelet-derived growth factor on transcriptional and post-transcriptional levels and are expressed coordinately with c-fos. Several of them have been found to encode likely transcriptional regulators that control the genetic program for growth. The goal of this proposed research is to understand how this genetic program is initiated by growth factors through the analysis of these tightly regulated immediate-early genes, which serve as an excellent paradigm for addressing this important regulatory problem. Five immediate-early genes have been selected for study. The signal transduction pathways involved in their activation will be examined. They will be isolated and characterized; their promoters and control regions will be defined: and the sequence requirements for serum induction will be determined. The mechanism through which transcription down-regulation occurs and the role of myc in the regulation of these genes will be examined. Two of them will then be analyzed further: the sequence requirements for activation by several growth factors will be determined, and protein factors that interact with these sequence elements will be identified. One such factor will be purified and cloned, and antibody reagents prepared for studying its function.
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