Repression of p15INK4b expression by Myc through association with Miz-1
Author: ["Peter Staller","Karen Peukert","Astrid Kiermaier","Joan Seoane","Jiri Lukas","Holger Karsunky","Tarik Möröy","Jiri Bartek","Joan Massagué","Frank Hänel","Martin Eilers"]
Publication: Nature Cell Biology
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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 p15INK4b by binding to the initiator element of the p15INK4b 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 p15INK4b that is associated with cellular senescence; conversely, deletion of c-myc in an established cell line activates p15INK4b expression. Alleles of c-myc that are unable to bind to Miz-1 fail to inhibit accumulation of p15INK4b messenger RNA in primary cells and are, as a consequence, deficient in immortalization.
Cite this article
Staller, P., Peukert, K., Kiermaier, A. et al. Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol 3, 392–399 (2001). https://doi.org/10.1038/35070076
