Myc Activation of Cyclin E/Cdk2 Kinase Involves Induction of Cyclin E Gene Transcription and Inhibition of p27(Kip1) Binding to Newly Formed Complexes

Oncogene. 1997 May 22;14(20):2373-81. doi: 10.1038/sj.onc.1201197.

Abstract

Induction of the Myc-oestrogen receptor fusion protein (MycER) by 4-OH-tamoxifen (OHT) leads to the activation of Cyclin E/Cyclin-dependent kinase 2 (CycE/Cdk2) complexes followed by the induction of DNA synthesis. As CycE/Cdk2 activity is essential for G1/S transition, we have investigated the mechanism by which Myc can activiate CycE/Cdk2. Our results suggest that this activation may involve at least two Myc-dependent steps: the induction of cyclin E gene transcription followed by accumulation of cyclin E mRNA in a protein synthesis-independent manner and the inhibition of p27(Kip1) association with CycE/Cdk2 complexes containing newly synthesised CycE. As a consequence phosphorylation of CycE-bound Cdk2 by cyclin activating kinase (CAK) is accelerated. We propose a model in which the active newly synthesised CycE/Cdk2 complexes trigger a positive feed-back mechanism to activate preexisting complexes through phosphorylation-dependent p27(Kip1) release.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins*
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / genetics*
  • Cyclins / metabolism
  • Enzyme Activation / genetics
  • Fibroblasts
  • Genes, myc / physiology*
  • Microtubule-Associated Proteins / metabolism*
  • Phosphorylation
  • RNA, Messenger / metabolism
  • Rats
  • Transcription, Genetic*
  • Tumor Suppressor Proteins*

Substances

  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Cyclins
  • Microtubule-Associated Proteins
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27