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

P Staller; K Peukert; A Kiermaier; J Seoane; J Lukas; H Karsunky; T Möröy; J Bartek; J Massagué; F Hänel; M Eilers

doi:10.1038/35070076

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

Nat Cell Biol. 2001 Apr;3(4):392-9. doi: 10.1038/35070076.

Authors

P Staller¹, K Peukert, A Kiermaier, J Seoane, J Lukas, H Karsunky, T Möröy, J Bartek, J Massagué, F Hänel, M Eilers

Affiliation

¹ Institute of Molecular Biology and Tumour Research, Emil Mannkopff Strabetae 2, 35033 Marburg, Germany.

PMID: 11283613
DOI: 10.1038/35070076

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Animals
Carrier Proteins / biosynthesis*
Cell Cycle Proteins*
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Gene Expression Regulation
HeLa Cells
Humans
Kruppel-Like Transcription Factors
Mice
Nuclear Proteins / metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins c-myc / metabolism*
Rats
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Trans-Activators / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Suppressor Proteins*
Zinc Fingers*

Substances

CDKN2B protein, human
Carrier Proteins
Cdkn2b protein, mouse
Cdkn2b protein, rat
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16
DNA-Binding Proteins
Kruppel-Like Transcription Factors
Nuclear Proteins
Proto-Oncogene Proteins c-myc
Recombinant Fusion Proteins
Trans-Activators
Transcription Factors
Tumor Suppressor Proteins
ZBTB17 protein, human