c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt's lymphoma cells.

Gregory MA, Hann SR
Mol Cell Biol. 2000 20 (7): 2423-35

PMID: 10713166 · PMCID: PMC85426 · DOI:10.1128/MCB.20.7.2423-2435.2000

The c-Myc oncoprotein is a transcription factor which is a critical regulator of cellular proliferation. Deregulated expression of c-Myc is associated with many human cancers, including Burkitt's lymphoma. The c-Myc protein is normally degraded very rapidly with a half-life of 20 to 30 min. Here we demonstrate that proteolysis of c-Myc in vivo is mediated by the ubiquitin-proteasome pathway. Inhibition of proteasome activity blocks c-Myc degradation, and c-Myc is a substrate for ubiquitination in vivo. Furthermore, an increase in c-Myc stability occurs in mitotic cells and is associated with inhibited c-Myc ubiquitination. Deletion analysis was used to identify regions of the c-Myc protein which are required for rapid proteolysis. We found that a centrally located PEST sequence, amino acids 226 to 270, is necessary for rapid c-Myc degradation, but not for ubiquitination. Also, N-terminal sequences, located within the first 158 amino acids of c-Myc, are necessary for both efficient c-Myc ubiquitination and subsequent degradation. We found that c-Myc is significantly stabilized (two- to sixfold) in many Burkitt's lymphoma-derived cell lines, suggesting that aberrant c-Myc proteolysis may play a role in the pathogenesis of Burkitt's lymphoma. Finally, mutation of Thr-58, a major phosphorylation site in c-Myc and a mutational hot spot in Burkitt's lymphoma, increases c-Myc stability; however, mutation of c-Myc is not essential for stabilization in Burkitt's lymphoma cells.

MeSH Terms (20)

3T3 Cells Amino Acid Sequence Animals Burkitt Lymphoma COS Cells Cysteine Endopeptidases Cysteine Proteinase Inhibitors Humans Mice Mitosis Molecular Sequence Data Multienzyme Complexes Mutation Neoplasm Proteins Proteasome Endopeptidase Complex Proto-Oncogene Proteins c-myc Sequence Deletion Transfection Tumor Cells, Cultured Ubiquitins

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