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

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


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*


  • 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