Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants (Nature, 436:807-811, 11 August 2005)

報告日期: 2005/09/30
報告時間: 15:10/16:00
報告學生: 黃冠誠
講評老師: 張敏政
附件下載:
Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants

Nature 436:807~811;2005

學生:黃冠誠

講評老師:張敏政

日期:94/09/30 3:10 pm

地點:602教室

 

The c-myc gene was discovered as the cellular homolog of the retroviral v-myc oncogene 27 years ago. .The family of myc genes are B-myc, C-myc, L-myc, N-myc, s-myc; howevere, only C-myc, L-myc, N-myc are neoplastic potential. Increased wild-type MYC expression occurs frequently in human cancers, except in Burkitt's lymphoma, where the translocated MYC allele is frequently mutated at several hotspots, including a major one at threonine-58. Acute MYC expression increases p53 or ARF levels and induces apoptosis, and previous transgenic animal studies revealed frequent inactivating mutations of p53 or p19ARF in transgenic Myc-induced lymphomas. Lowe and coworkers demonstrate that wild-type MYC can also trigger apoptosis by inducing Bim, which neutralizes Bcl-2. In contrast, the MYC point mutants failed to induce Bim, promoting murine lymphomas that escaped both wild-type p53 and p19ARF, and in doing so, evaded apoptosis.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.

 

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