The c-Myc transactivation domain is a direct modulator of apoptotic versus proliferative signals.
We have assayed the oncogenic, proliferative, and apoptotic activities of the 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; however, the most frequent Burkitt's lymphoma allele (T58I) had an unexpected substantial decrease in transforming activity (85%). All alleles restored the proliferation function of c-Myc in cells that grow slowly due to a c-myc knockout. There was discordance for some alleles between apoptotic and oncogenic activities, but only the T58A allele had elevated transforming activity with a concomitant reduced apoptotic potential. We discovered a novel missense mutation, MycS71F, that had a very low apoptotic activity compared to wild-type Myc, yet this mutation has never been found in lymphomas, suggesting that there is no strong selection for antiapoptotic c-Myc alleles. MycS71F also induced very low levels of cytochrome c release from mitochondria, suggesting a mechanism of action for this mutation. Phosphopeptide mapping provided a biochemical basis for the dramatically different biological activities of the transformation-defective T58I and transformation-enhanced T58A c-Myc alleles. Furthermore, the antiapoptotic survival factor insulin-like growth factor 1 was found to suppress phosphorylation of T58, suggesting that the c-Myc transactivation domain is a direct target of survival signals.
Chang
D W
DW
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Claassen
G F
GF
Hann
S R
SR
Cole
M D
MD
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D005786:Gene Expression Regulation; D016259:Genes, myc; D006801:Humans; D020125:Mutation, Missense; D014162:Transfection