Editors' ChoiceCancer

Mapping the c-MYC Oncogene-Induced Pathway to Cell Death

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Science's STKE  09 Jan 2007:
Vol. 2007, Issue 368, pp. tw10
DOI: 10.1126/stke.3682007tw10

Cancer is often caused by cells that show not only excessive proliferation but also resistance to apoptosis. Thus, deciphering the signaling pathways that are disrupted in transformed cells that become resistant to apoptosis may provide insights for the control of human cancer. For example, the oncoprotein c-MYC, an important contributor to human tumors, acts both to increase proliferation and to promote cell death. Myc is a transcription factor that can both activate and repress gene transcription and thus influences many potential targets that might contribute to regulation of apoptosis. Patel and McMahon extended earlier studies showing that binding of Myc to another transcription factor, MIZ-1, and inhibition of MIZ-1-dependent transcription were important for promotion of apoptosis by c-MYC. The new work shows that a critical target of MIZ-1 is the antiapoptotic protein BCL2. In cultured human diploid fibroblasts, a form of c-MYC (c-MYCV394D) that fails to interact with MIZ-1 was also defective in inducing apoptosis. Furthermore, if expression of MIZ-1 was reduced in these cells by expression of short hairpin RNA (shRNA), the apoptotic effect of c-MYCV394D was restored, indicating that MIZ-1 is a key target of c-MYC in controlling apoptosis. However, MIZ-1 activates transcription of several hundred genes, and the authors wanted to know which were necessary and/or sufficient to reproduce the effects of MIZ-1 to promote cell survival. A search of the MIZ-1 target genes revealed in microarrays yielded a likely candidate--the gene encoding the antiapoptotic protein BCL2. Indeed, expression of BCL2 was decreased by wild-type c-MYC but not by the c-MYCV394D mutant, and inhibition of expression of BCL2 by shRNA rescued the effect of c-MYCV394D to promote apoptosis. Many earlier studies of mouse models and of human tumor cells have shown that BCL2 and c-MYC appear to work together in promoting cancer. At least in certain cell types, the new results indicate that transcription of the BCL2 gene is the essential target regulated through c-MYC and MIZ-1, thus providing a mechanistic explanation for the observed cooperation of BCL-2 and c-MYC in tumorigenesis.

J. H. Patel, S. B. McMahon, BCL2 is a downstream effector of MIZ-1 essential for blocking c-MYC-induced apoptosis. J. Biol. Chem. 282, 5-13 (2007). [Abstract] [Full Text]

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