Disruption of TGF-β growth inhibition by oncogenic ras is linked to p27(kip1) mislocalization

Xuedong Liu, Yin Sun, Marcelo Ehrlich, Trent Lu, Yoel Kloog, Robert A. Weinberg, Harvey F. Lodish, Yoav I. Henis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Expression of oncogenic Ras in epithelial tumor cells is linked to the loss of transforming growth factor-β (TGF-β) anti-proliferative activity, and was proposed to involve inhibition of Smad2/3 nuclear translocation. Here we studied several epithelial cell lines expressing oncogenic N-Ras(K61) and show that TGF-β-induced nuclear translocation of and transcriptional activation by Smad2/3 were unaffected. In contrast, oncogenic Ras mediated nuclear-to-cytoplasmic mislocalization of p27(Kip1) (p27) and of the cyclin-dependent kinase (CDK) CDK6, but not CDK2. Concomitantly, oncogenic Ras abrogated the ability of TGF-β to release p27 from CDK6, to enhance its binding to CDK2 and to inhibit CDK2 activity. Inactivation of Ras by a specific antagonist restored the growth inhibitory response to TGF-β with concurrent normalization of p27 and CDK6 localization. Therefore, the disruption of TGF-β-mediated growth inhibition by oncogenic Ras appears to be due to lack of inhibition of CDK2, caused by the sequestration of p27 and CDK2 in different subcellular compartments and by the loss of TGF-β-induced partner switching of p27 from CDK6 to CDK2.

Original languageEnglish
Pages (from-to)5926-5935
Number of pages10
JournalOncogene
Volume19
Issue number51
DOIs
StatePublished - 30 Nov 2000

Funding

FundersFunder number
Robert Steel Foundation for Pediatric Cancer Research
National Institutes of Health
National Cancer Institute
Israel Cancer Research Fund
Israel Academy of Sciences and Humanities
Israel Science Foundation

    Keywords

    • Mislocalization of p27(Kip1)
    • Oncogenic Ras
    • TGF-β growth inhibition
    • p27(Kip1) partner switching

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