c-Myc hot spot mutations in lymphomas result in inefficient ubiquitinationand decreased proteasome-mediated turnover

The c-myc proto-oncogene encodes a short-lived transcription factor that pl ays an important role in cell cycle regulation, differentiation and apoptos is, c-myc is often rearranged in tumors resulting in deregulated expression . In addition, mutations in the coding region of c-myc are frequently found in human lymphomas, a hot spot being the Thr58 phosphorylation site, a mut ation shown to enhance the transforming capacity of c-Myc, It Is, however, still unclear in what way this mutation affects c-Myc activity, Our resuits show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that abol ish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over at normal rates In these cells. Myc Thr58 mu tants expressed ectopically in other cell types also exhibit reduced protea some-mediated degradation, which correlates with a substantial decrease in their ubiquitination, These results suggest that ubiquitin/proteasome-media ted degradation of c-Myc is triggered by Thr58 phosphorylation revealing a new important level of control of c-Myc activity. Mutation of Thr58 in lymp homa thus escapes this regulation resulting In accumulation of c-Myc protei n, likely as part of the tumor progression, (C) 2000 by The American Societ y of Hematology.