The c-myc transactivation domain is a direct modulator of apoptotic versusproliferative signals

We have assayed the oncogenic, proliferative, and apoptotic activities of t he frequent mutations that occur in the c-myc gene in Burkitt's lymphomas. Some alleles have a modest (50 to 60%) increase in transforming activity; h owever, the most frequent Burkitt's Lymphoma allele (T58I) had an unexpecte d substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-m yc knockout. There was discordance for some alleles between apoptotic and o ncogenic activities, but only the T58A allele had elevated transforming act ivity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compare d to wild-type Myc, yet this mutation has never been found in lymphomas, su ggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochon dria, suggesting a mechanism of action for this mutation. Phosphopeptide ma pping provided a biochemical basis for the dramatically different biologica l activities of the transformation-defective T58I and transformation-enhanc ed T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insul in-like growth factor 1 was found to suppress phosphorylation of T58, sugge sting that the c-Myc transactivation domain is a direct target of survival signals.