The considerable interest focused on c-myc stems from the correlation of c-myc expression with cellular proliferation and from the association of an """"""""activated"""""""" myc with a wide variety of tumors in diverse species including human. The overall goal of this proposal is to determine if the differential synthesis of the two major c-myc proteins (I and II) has a role in the control of cellular proliferation and oncogenesis. The two c-myc proteins were found to differ from one another by an N-terminal extension due to initation at two distinct sites. The larger form (c-myc I) initiates at a unique non-ATG codon in exon 1 and was dramatically induced as cells became density-inhibited. In addition, there were significant changes found in the ratios of c- myc I and II in cells which contain an """"""""activated"""""""" c-myc gene. The regulation of c-myc I and II protein during proliferation was also found to be altered in bursal lymphoma cell lines. The factors and mechanisms which control the differential synthesis of the two c-myc proteins will be studied. Specific growth stimulatory and inhibitory factors and conditions will be tested in a variety of cell types for their ability to dissociate c-myc I and II synthesis. The influence of mRNA structure and initiation factors on the differential initiation site usage will be examined in normal cells. In lymphoma cells with an """"""""activated"""""""" c-myc, the effects of mutation, proviral integration site and promotor usage on c- myc synthesis will be examined. Finally, differences in c-myc I and II function will be examined by establishing cell lines which overexpress either c-myc I or II. This will be accomplished by site-directed mutagenesis of the initiation codons. The ability of each c-myc protein to cotransform cells with ras, to cause tumors and anchorage independence, to growth factor requirements, to alter growth studies should establish if there are any major differences in c-myc I and II synthesis, regulation and function during proliferation and oncogenesis by known techniques and assays.
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