title: Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms.
abstract: Platelet-derived growth factor-BB (PDGF-BB) acts as a full mitogen for cultured aortic smooth muscle cells (SMC), promoting DNA synthesis and cell proliferation. In contrast, angiotensin II (Ang II) induces cellular hypertrophy as a result of increased protein synthesis, but is unable to drive cells into S phase. In an effort to understand the molecular basis for this differential growth response, we have examined the downstream effects of PDGF-BB and Ang II on regulators of the cell cycle machinery in rat aortic SMC. Both PDGF-BB and Ang II were found to stimulate the accumulation of G(1) cyclins with similar kinetics. In addition, little difference was observed in the expression level of their catalytic partners, Cdk4 and Cdk2. However, while both factors increased the enzymatic activity of Cdk4, only PDGF-BB stimulated Cdk2 activity in late G(1) phase. The lack of activation of Cdk2 in Ang II-treated cells was causally related to the failure of Ang II to stimulate phosphorylation of the enzyme on threonine and to downregulate p27(Kip1) expression. By contrast, exposure to PDGF-BB resulted in a progressive and dramatic reduction in the level of p27(Kip1) protein. The time course of p27(Kip1) decline was correlated with a reduced rate of synthesis and an increased rate of degradation of the protein. Importantly, the repression of p27(Kip1) synthesis by PDGF-BB was associated with a marked attenuation of Kip1 gene transcription and a corresponding decrease in Kip1 mRNA accumulation. We also show that the failure of Ang II to promote S phase entry is not related to the autocrine production of transforming growth factor-beta1 by aortic SMC. These results identify p27(Kip1) as an important regulator of the phenotypic response of vascular SMC to mitogenic and hypertrophic stimuli.
authors.affiliation: Research Centre, Centre hospitalier de l'Université de Montréal and Department of Pharmacology, University of Montreal, Montreal, Quebec, H2W 1T8 Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Servant
authors.forename: P
authors.initials: P
authors.lastname: Coulombe
authors.forename: B
authors.initials: B
authors.lastname: Turgeon
authors.forename: S
authors.initials: S
authors.lastname: Meloche
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D008934:Mitogens / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D051381:Rats; D016196:S Phase; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077214:Becaplermin; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases