Altered complex formation between p21waf, p27kip and their partner G1 cyclins determines the stimulatory or inhibitory transforming growth factor-beta1 growth response of human fibroblasts.
TGF-beta1 stimulates proliferation of WI38 human embryo fibroblasts but inhibits that of their SV40-transformed counterparts, VA13 cells. Protein expression levels of cyclins A, D1, E and that of cdk2 and cdk4 were not affected by TGF-beta1 in either of these cells. However, TGF-beta1-treatment increases cdk2 kinase activity in WI38 cells and reduces it in VA13 cells. The same treatment reduces the amount of p21waf present in complexes with cyclins D1 and E in growth-stimulated WI38 cells, but the reverse applies in growth-inhibited VA13 cells. Mitogenic stimulation of WI38 fibroblasts correlated with decreased expression of p27kip protein and reduced amounts of it in complex with cyclin E. In contrast, proliferative inhibition of VA13 fibroblasts by TGF-beta1 caused a reduction of p27kip in complexes with cyclin D1, but increased it in complexes with cyclin E, without affecting the overall level of p27kip protein expression. Thus, in this human fibroblast model, TGF-beta1-mediated stimulation or inhibition of proliferation depends on modulation in the amounts of p21waf and p27kip in complexes with cyclins D1 and E.
Dkhissi
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UPR 9079 du CNRS, BP no. 8, 94801 Villejuif, France.
Raynal
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S
Lawrence
D A
DA
D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D056746:Cyclin G; D056766:Cyclin G1; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D013539:Simian virus 40; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
C534702:CCNG1 protein, human; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495900:CDK4 protein, human; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases