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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 2104-2110
c-Myc hot spot mutations in lymphomas result in inefficient
ubiquitination and decreased proteasome-mediated turnover
Fuad Bahram,
Natalie von der Lehr,
Cihan Cetinkaya, and
Lars-Gunnar Larsson
From the Department of Plant Biology, Uppsala Genetic Center,
Swedish University of Agricultural Sciences, and Department of Genetics
and Pathology, University of Uppsala, University Hospital, Uppsala,
Sweden.
The c-myc proto-oncogene encodes a short-lived transcription
factor that plays an important role in cell cycle regulation, differentiation and apoptosis. 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 mutation
shown to enhance the transforming capacity of c-Myc. It is, however, still unclear in what way this mutation affects c-Myc activity. Our
results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58
or other mutations that abolish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over
at normal rates in these cells. Myc Thr58 mutants expressed ectopically
in other cell types also exhibit reduced proteasome-mediated degradation, which correlates with a substantial decrease in their ubiquitination. These results suggest that
ubiquitin/proteasome-mediated degradation of c-Myc is triggered by
Thr58 phosphorylation revealing a new important level of control of
c-Myc activity. Mutation of Thr58 in lymphoma thus escapes this
regulation resulting in accumulation of c-Myc protein, likely as part
of the tumor progression.
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