细胞周期蛋白依赖性激酶6（Cdk6）的异位表达可规避转化生长因子-β介导的生长抑制。

Ectopic expression of Cdk6 circumvents transforming growth factor-beta mediated growth inhibition.

作者信息

Zhang F, Taipale M, Heiskanen A, Laiho M

机构信息

Haartman Institute, Department of Virology, University of Helsinki, FIN-00014 Helsinki, Finland.

出版信息

Oncogene. 2001 Sep 13;20(41):5888-96. doi: 10.1038/sj.onc.1204745.

DOI:10.1038/sj.onc.1204745

PMID:11593394

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.

摘要

转化生长因子-β（TGF-β）诱导的细胞生长停滞涉及对D型和E型细胞周期蛋白激酶复合物活性的调节，这一调节过程主要被认为是通过对p15（Ink4b）和p27（Kip1）细胞周期蛋白激酶抑制剂的调节来介导的。我们在此表明，TGF-β可下调Cdk6，并且在Mv1Lu貂上皮细胞中瞬时和稳定表达Cdk6可克服TGF-β介导的停滞。异位表达Cdk6的主要作用是隔离TGF-β诱导的p15（Ink4b），并在细胞周期蛋白D复合物中维持更多的p27（Kip1），从而防止TGF-β引起的p27（Kip1）向Cdk2的完全转移。这导致了活性细胞周期蛋白D-Cdk6-p27（Kip1）复合物和部分活性细胞周期蛋白E-Cdk2复合物的存在，并导致TGF-β无法完全阻止Mv1Lu细胞生长。尽管在细胞中类似表达的显性负性Cdk6隔离了p15（Ink4b）和p27（Kip1），但它缺乏激酶活性，无法克服TGF-β的停滞作用。结果表明，TGF-β在G1期停滞的执行过程中需要下调Cdk6激酶，这会导致p15（Ink4b）和p27（Kip1）抑制剂与D型和E型细胞周期蛋白激酶复合物结合的变化。