Induction of anchorage-independent growth by transforming growth factor-beta linked to anchorage-independent expression of cyclin D1.
Transforming growth factor-beta (TGF-beta) was originally identified, characterized, and named on the basis of its ability to induce anchorage-independent growth (phenotypic transformation). This effect has received little attention in recent years, probably because the induction of anchorage-independent growth by TGF-beta has been observed only in a few cell lines, of which NRK fibroblasts are among the best studied. We have previously reported that normal rat kidney cells have lost their normal adhesion requirement for expression of cyclin D1, and we now show that this loss is causal for the induction of anchorage-independent growth by TGF-beta. First, we show that TGF-beta fails to induce anchorage-independent growth in NIH-3T3 cells and human fibroblasts that have retained their adhesion requirement for expression of cyclin D1. Second, we show that TGF-beta complements rather than affects cyclin D-cdk4/6 kinase activity in NRK cells. Third, we show that forced expression of cyclin D1 in suspended 3T3 cells renders them susceptible to transformation by TGF-beta. These results may explain why the induction of anchorage-independent growth by TGF-beta is a rare event and yet also describe a molecular scenario in which the mesenchymal response to TGF-beta could indeed involve the acquisition of an anchorage-independent phenotype.
Zhu
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X
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19087, USA.
Scharf
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E
Assoian
R K
RK
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis*; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases