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Ectopic expression of Cdk6 circumvents transforming growth factor-beta mediated growth inhibition.
Oncogene. 2001 Sep 13; 20(41):5888-96.O

Abstract

Transforming growth factor-beta (TGF-beta) 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 p15(Ink4b) and p27(Kip1) cyclin kinase inhibitors. We show here that TGF-beta downregulates Cdk6 and that transient and stable expression of Cdk6 in Mv1Lu mink epithelial cells overrides TGF-beta mediated arrest. The main effect of the ectopic Cdk6 expression was to sequester TGF-beta induced p15(Ink4b) and to maintain more p27(Kip1) in cyclin D-complexes preventing the complete shift of p27(Kip1) to Cdk2 invoked by TGF-beta. This led to the presence of an active cyclinD-Cdk6-p27(Kip1) complex and partially active cyclin E-Cdk2 complex and resulted in the failure of TGF-beta to fully arrest Mv1Lu cell growth. Though dominant negative Cdk6, expressed similarly in the cells, sequestered both p15(Ink4b) and p27(Kip1), it lacks kinase activity and was unable to override the TGF-beta arrest. The results demonstrate that downregulation of Cdk6 kinase is required for the enforcement of the G(1)-phase arrest by TGF-beta and results in changes in association of the p15(Ink4b) and p27(Kip1) inhibitors with D- and E-type cyclin kinase complexes.

Authors+Show Affiliations

Haartman Institute, Department of Virology, University of Helsinki, FIN-00014 Helsinki, Finland.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

11593394

Citation

Zhang, F, et al. "Ectopic Expression of Cdk6 Circumvents Transforming Growth Factor-beta Mediated Growth Inhibition." Oncogene, vol. 20, no. 41, 2001, pp. 5888-96.
Zhang F, Taipale M, Heiskanen A, et al. Ectopic expression of Cdk6 circumvents transforming growth factor-beta mediated growth inhibition. Oncogene. 2001;20(41):5888-96.
Zhang, F., Taipale, M., Heiskanen, A., & Laiho, M. (2001). Ectopic expression of Cdk6 circumvents transforming growth factor-beta mediated growth inhibition. Oncogene, 20(41), 5888-96.
Zhang F, et al. Ectopic Expression of Cdk6 Circumvents Transforming Growth Factor-beta Mediated Growth Inhibition. Oncogene. 2001 Sep 13;20(41):5888-96. PubMed PMID: 11593394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ectopic expression of Cdk6 circumvents transforming growth factor-beta mediated growth inhibition. AU - Zhang,F, AU - Taipale,M, AU - Heiskanen,A, AU - Laiho,M, PY - 2001/03/19/received PY - 2001/05/31/revised PY - 2001/06/18/accepted PY - 2001/10/11/pubmed PY - 2001/11/3/medline PY - 2001/10/11/entrez SP - 5888 EP - 96 JF - Oncogene JO - Oncogene VL - 20 IS - 41 N2 - Transforming growth factor-beta (TGF-beta) 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 p15(Ink4b) and p27(Kip1) cyclin kinase inhibitors. We show here that TGF-beta downregulates Cdk6 and that transient and stable expression of Cdk6 in Mv1Lu mink epithelial cells overrides TGF-beta mediated arrest. The main effect of the ectopic Cdk6 expression was to sequester TGF-beta induced p15(Ink4b) and to maintain more p27(Kip1) in cyclin D-complexes preventing the complete shift of p27(Kip1) to Cdk2 invoked by TGF-beta. This led to the presence of an active cyclinD-Cdk6-p27(Kip1) complex and partially active cyclin E-Cdk2 complex and resulted in the failure of TGF-beta to fully arrest Mv1Lu cell growth. Though dominant negative Cdk6, expressed similarly in the cells, sequestered both p15(Ink4b) and p27(Kip1), it lacks kinase activity and was unable to override the TGF-beta arrest. The results demonstrate that downregulation of Cdk6 kinase is required for the enforcement of the G(1)-phase arrest by TGF-beta and results in changes in association of the p15(Ink4b) and p27(Kip1) inhibitors with D- and E-type cyclin kinase complexes. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/11593394/Ectopic_expression_of_Cdk6_circumvents_transforming_growth_factor_beta_mediated_growth_inhibition_ L2 - https://doi.org/10.1038/sj.onc.1204745 DB - PRIME DP - Unbound Medicine ER -