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- Title
Repression of p15<sup>INK4b</sup> expression by Myc through association with Miz-1.
- Authors
Staller, Peter; Peukert, Karen; Kiermaier, Astrid; Seoane, Joan; Lukas, Jiri; Karsunky, Holger; Möröy, Tarik; Bartek, Jiri; Massagué, Joan; Hänel, Frank; Eilers, Martin
- Abstract
Deregulated expression of c-myc can induce cell proliferation in established cell lines and in primary mouse embryonic fibroblasts (MEFs), through a combination of both transcriptional activation and repression by Myc. Here we show that a Myc-associated transcription factor, Miz-1, arrests cells in G1 phase and inhibits cyclin D-associated kinase activity. Miz-1 upregulates expression of the cyclin-dependent kinases (CDK) inhibitor p15[sup INK4b] by binding to the initiator element of the p15[sup INK4b] promoter. Myc and Max form a complex with Miz-1 at the p15 initiator and inhibit transcriptional activation by Miz-1. Expression of Myc in primary cells inhibits the accumulation of p15[sup INK4b] that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15[sup INK4b] expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15[sup INK4b] messenger RNA in primary cells and are, as a consequence, deficient in immortalization.
- Publication
Nature Cell Biology, 2001, Vol 3, Issue 4, p392
- ISSN
1465-7392
- Publication type
Academic Journal
- DOI
10.1038/35070076