Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants

Hemann, M. T., Bric, A., Teruya-Feldstein, J., Herbst, A., Nilsson, J. A., Cordon-Cardo, C., Cleveland, J. L., Tansey, W. P., Lowe, S. W. (August 2005) Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants. Nature, 436 (7052). pp. 807-11. ISSN 1476-4687 (Electronic)

URL: https://www.ncbi.nlm.nih.gov/pubmed/16094360
DOI: 10.1038/nature03845

Abstract

The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.

Item Type: Paper
Uncontrolled Keywords: Adoptive Transfer Alleles Animals Apoptosis Apoptosis Regulatory Proteins Burkitt Lymphoma genetics metabolism pathology Carrier Proteins metabolism Cell Cycle Proteins metabolism Cell Proliferation Cyclin-Dependent Kinase Inhibitor p16 Cyclin-Dependent Kinase Inhibitor p21 Genes, myc genetics Humans Membrane Proteins metabolism Mice Mice Inbred C57BL Mutation genetics Proto-Oncogene Proteins metabolism Proto-Oncogene Proteins c-bcl-2 metabolism Proto-Oncogene Proteins c-myc genetics/ metabolism Stem Cell Transplantation Tumor Suppressor Protein p14ARF metabolism Tumor Suppressor Protein p53 metabolism
Subjects: diseases & disorders > cancer
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: CSHL Librarian
Date: 11 August 2005
Date Deposited: 12 Jan 2012 17:48
Last Modified: 03 May 2018 20:26
PMCID: PMC4599579
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22591

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