TY - JOUR
T1 - Disruption of TGF-β growth inhibition by oncogenic ras is linked to p27(kip1) mislocalization
AU - Liu, Xuedong
AU - Sun, Yin
AU - Ehrlich, Marcelo
AU - Lu, Trent
AU - Kloog, Yoel
AU - Weinberg, Robert A.
AU - Lodish, Harvey F.
AU - Henis, Yoav I.
N1 - Funding Information:
This work was supported in part by grants from the Israel Science Foundation administered by the Israel Academy of Sciences and Humanities and from the Israel Cancer Research Fund (YI Henis), by a National Cancer Institute grant (RA Weinberg), and by a National Institutes of Health grant (HF Lodish). RA Weinberg is an American Cancer Society Research Professor and a Daniel K Ludwig Cancer Research Professor. X Liu was supported by postdoctoral fellowships from the NIH and the US Army Breast Cancer Research Program. Y Sun was supported by a Robert Steel Foundation for Pediatric Cancer Research postdoctoral fellowship. We thank Drs J Kato, T Kitamura and JL Bos for expression vectors, Dr P Howe for HT1080 cells, Dr X Hua for the HT1080 cDNA library and R&D Systems for TGF-b1.
PY - 2000/11/30
Y1 - 2000/11/30
N2 - 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.
AB - 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.
KW - Mislocalization of p27(Kip1)
KW - Oncogenic Ras
KW - TGF-β growth inhibition
KW - p27(Kip1) partner switching
UR - http://www.scopus.com/inward/record.url?scp=0034735895&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1203991
DO - 10.1038/sj.onc.1203991
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AN - SCOPUS:0034735895
SN - 0950-9232
VL - 19
SP - 5926
EP - 5935
JO - Oncogene
JF - Oncogene
IS - 51
ER -
