Our recent results on the function of alternative translational forms and phosphorylation of c-Myc have led us to change our ideas on how c-Myc functions at the molecular level to control growth and apoptosis. We have identified a naturally occurring, downstream- initiated form of c-Myc, termed dMyc, which lacks the N-terminal 100 amino acids. Since it has a severely-truncated transactivation domain, it cannot transactivate through the c-Myc """"""""E"""""""" box DNA binding site. Surprisingly, however, dMyc retains the ability of the full-length c-Myc protein to stimulate proliferation and anchorage-independent growth and induce apoptosis in low serum. We also have data to suggest that several N-terminal c-Myc phosphorylation events, including novel tyrosine phosphorylation by c-Src, appear to be inhibitory to c-Myc function. Therefore, our hypothesis is that transactivation through the EMS Myc/Max element is not necessary for at least some of the biological functions of c-Myc and that the N-terminal 100 amino acids of c-Myc represent an inhibitory domain which modulates the function of c-Myc. In addition, interactions through the N-terminal region with specific regulatory proteins are important for the function and inhibition of function of c-Myc and that these interactions are modulated through specific and regulated phosphorylation events. The following specific aims are designed to test this hypothesis: Specific l focuses on determining the biological and mechanistic role of novel N-terminal phosphorylations for c-Myc function, including N-terminal tyrosine phosphorylation by c-Src and highly- regulated N-terminal serine/threonine phosphorylations.
Specific Aim 2 will be to determine the biological role and molecular properties of dMyc in comparison to the full-length c-Myc protein. Finally, Specific Aim 3 will focus on determining the role of B-Myc and B-Myc phosphorylation in regulating the biological and molecular functions of c-Myc. B-Myc affords an excellent model to examine the N-terminal region since it is a small protein homologous to the N-terminal domain of c-Myc. Our preliminary results and the results of experiments proposed in these specific aims will have major implications for the function of c-Myc.
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