c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover.
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. (Blood. 2000;95:2104-2110)
Bahram
F
F
Department of Plant Biology, Uppsala Genetic Center, Swedish University of Agricultural Sciences, Uppsala, Sweden.
von der Lehr
N
N
Cetinkaya
C
C
Larsson
L G
LG
D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D000090063:Proto-Oncogene Mas; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism*
C000715470:MAS1 protein, human; D009097:Multienzyme Complexes; D000090063:Proto-Oncogene Mas; D014452:Ubiquitins; D013912:Threonine; D011392:Proline; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex