Repression of p15INK4b expression by Myc through association with Miz-1.

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.
Mesh Terms:
3T3 Cells, Animals, Carrier Proteins, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Gene Expression Regulation, Hela Cells, Humans, Kruppel-Like Transcription Factors, Mice, Nuclear Proteins, Promoter Regions, Genetic, Proto-Oncogene Proteins c-myc, Rats, Recombinant Fusion Proteins, Trans-Activators, Transcription Factors, Tumor Suppressor Proteins, Zinc Fingers
Nat. Cell Biol.
Date: Apr. 01, 2001
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