FUNCTION OF THE C-MYC ONCOGENE

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Mutations that disrupt the regulation or expression level of the c-myc gene are frequently found in human and animal cancers. Ectopic expression studies define numerous biological activities of the c-myc gene, including transformation, immortalization, blockage of cell differentiation and induction of apoptosis. Since the Myc proteins bind to specific DNA sequences, the mechanisms of cell transformation can be viewed as that of a transcription factor that activates specific target genes. Functional studies have demonstrated that two specific domains of the c-Myc protein are essential for cell transformation: the C-terminal 100 amino acids which encompass the DNA binding region, and a small 20 amino acid segment from the N-terminus (called Myc Box 2) that is conserved in all members of the myc family of genes. Since the DNA binding region is well characterized, the major functional domain of the c-Myc protein that remains undefined is Myc Box 2. This project will address the function of Myc Box 2 through an analysis of the nuclear proteins that bind to this region and which are also essential for the transforming activity of the oncogene. The experimental approach is based on preliminary studies i which dominant interfering alleles of the c-Myc protein were shown to form protein complexes that are dependent on the integrity of Myc Box 2 and hence correlate with nuclear factors that may be essential for c-Myc function. The specific aims are as follows: 1. An essential, rate-limiting nuclear factor (termed MB2F) which binds to the c-Myc amino terminus through Myc Box 2 will be purified biochemically and the corresponding cDNA will be cloned. 2. The function of MB2F will be addressed through studies of potential transforming activity and interactions with nuclear components. 3. The requirement of MB2F for transformation by other oncogenes will be assessed. In particular, we will test if MB2F is essential for transformation by another nuclear oncogene, the adenovirus E1a gene, and a tyrosine kinase oncogene, BCR-abl. 4. The potential regulation of c-Myc protein interaction with the MB2F cofactor by either extracellular stimuli or cell cycle progression will be studied. The long range goal of this project is to identify cellular promoters that are dependent on both c-Myc and MB2F for their activation and hence represent the downstream effectors of cell transformation.