Ectopic expression of Cdk6 circumvents transforming growth factor-β mediated growth inhibition

F. Zhang, M. Taipale, A. Heiskanen, Marikki Laiho

Research output: Contribution to journalArticle

Abstract

Transforming growth factor-β (TGF-β) induced growth arrest of cells involves regulation of the activities of both D- and E-type cyclin kinase complexes thought to be mediated primarily by the regulation of p15Ink4b and p27Kip1 cyclin kinase inhibitors. We show here that TGF-β downregulates Cdk6 and that transient and stable expression of Cdk6 in Mv1Lu mink epithelial cells overrides TGF-β mediated arrest. The main effect of the ectopic Cdk6 expression was to sequester TGF-β induced p15Ink4b and to maintain more p27Kip1 in cyclin D-complexes preventing the complete shift of p27Kip1 to Cdk2 invoked by TGF-β. This led to the presence of an active cyclinD-Cdk6-p27Kip1 complex and partially active cyclin E-Cdk2 complex and resulted in the failure of TGF-β to fully arrest Mv1Lu cell growth. Though dominant negative Cdk6, expressed similarly in the cells, sequestered both p15Ink4b and p27Kip1, it lacks kinase activity and was unable to override the TGF-β arrest. The results demonstrate that downregulation of Cdk6 kinase is required for the enforcement of the G1-phase arrest by TGF-β and results in changes in association of the p15Ink4b and p27Kip1 inhibitors with D- and E-type cyclin kinase complexes.

Original languageEnglish (US)
Pages (from-to)5888-5896
Number of pages9
JournalOncogene
Volume20
Issue number41
DOIs
StatePublished - Sep 13 2001
Externally publishedYes

Fingerprint

Transforming Growth Factors
Growth
Cyclin D
Phosphotransferases
Down-Regulation
Mink
Cyclin E
Cyclins
Ectopic Gene Expression
G1 Phase
Epithelial Cells

Keywords

  • Cell cycle regulation
  • Cyclin-dependent kinase
  • Cyclin-dependent kinase inhibitors
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Ectopic expression of Cdk6 circumvents transforming growth factor-β mediated growth inhibition. / Zhang, F.; Taipale, M.; Heiskanen, A.; Laiho, Marikki.

In: Oncogene, Vol. 20, No. 41, 13.09.2001, p. 5888-5896.

Research output: Contribution to journalArticle

Zhang, F. ; Taipale, M. ; Heiskanen, A. ; Laiho, Marikki. / Ectopic expression of Cdk6 circumvents transforming growth factor-β mediated growth inhibition. In: Oncogene. 2001 ; Vol. 20, No. 41. pp. 5888-5896.
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