TGF-β induced G1 cell cycle arrest requires the activity of the proteasome pathway

Fan Zhang, Mia Mönkkönen, Stina Roth, Marikki Laiho

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming growth factor-β TGF-β induces a potent G1/S-phase cell cycle arrest of epithelial cells by inhibiting the activities of cyclin D- and cyclin E-associated kinase complexes. Downregulation of the kinase activities is mediated by induction of cyclin dependent kinase (CDK) inhibitor p15Ink4b which blocks CDK4 and CDK6 kinases and leads to binding of p27Kip1 to CDK2-cyclin E complex. Levels of several of these factors are controlled by the ubiquitin-proteasome pathway. We demonstrate here that proteasomal inhibitors release the cells from TGF-β imposed G1-phase arrest and instigate the entry of the cells into S-phase. Proteasomal inhibitors are shown to specifically increase the activity of the cyclin D-kinase complex by increasing the levels of p27Kip1 and cyclin D and by maintaining CDK4/6 protein levels leading to phosphorylation of the retinoblastoma protein without increasing cyclin E-associated kinase activity. The results indicate caution in the potential therapeutic use of the proteasome inhibitors due to unscheduled initiation of DNA replication in the presence of a physiological growth inhibitor.

Original languageEnglish (US)
Pages (from-to)190-196
Number of pages7
JournalExperimental cell research
Volume281
Issue number2
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • CDK
  • Cell cycle
  • Proteasomal inhibitors
  • TGF-β

ASJC Scopus subject areas

  • Cell Biology

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