Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants Journal Article
| Authors: | Hemann, M. T.; Bric, A.; Teruya-Feldstein, J.; Herbst, A.; Nilsson, J. Å; Cordon-Cardo, C.; Cleveland, J. L.; Tansey, W. P.; Lowe, S. W. |
| Article Title: | Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants |
| 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. |
| Keywords: | controlled study; gene mutation; mutation; proto-oncogene proteins; nonhuman; mutant protein; cell proliferation; proteins; animal cell; mouse; animals; cell cycle proteins; mice; protein bcl 2; apoptosis; genes; gene expression; embryo; animal model; bim protein; apoptosis regulatory proteins; membrane proteins; alleles; gene function; stem cell transplantation; mice, inbred c57bl; carcinogenesis; tumorigenesis; tumor suppressor gene; b cell lymphoma; gene activation; tumors; myc protein; genes, myc; carrier proteins; tumor protein; carcinogenicity; protein induction; tumor suppressor protein p53; gene loss; adoptive transfer; cyclin-dependent kinase inhibitor p16; cyclin-dependent kinase inhibitor p21; tumor suppressor protein p14arf; proto-oncogene proteins c-myc; medicine; proto-oncogene proteins c-bcl-2; mutagenesis; burkitt lymphoma; oncogene myc; genetic transformation; tumor escape; stimulate proliferation |
| Journal Title: | Nature |
| Volume: | 436 |
| Issue: | 7052 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2005-08-11 |
| Start Page: | 807 |
| End Page: | 811 |
| Language: | English |
| DOI: | 10.1038/nature03845 |
| PUBMED: | 16094360 |
| PROVIDER: | scopus |
| PMCID: | PMC4599579 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 181" - "Export Date: 24 October 2012" - "CODEN: NATUA" - "Source: Scopus" |
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