Differential regulation of p27kip1 levels and CDK activities by hypertrophic and hyperplastic agents in vascular smooth muscle cells.
To understand the molecular mechanisms that determine the fate of a cell to undergo either hypertrophy or hyperplasia, we studied the effects of angiotensin II (Ang II) and platelet-derived growth factor (PDGF)-BB, hypertrophic and hyperplastic agents, respectively, on the modulation of G1/S transition molecules in smooth muscle cells. Ang II increased protein synthesis while PDGF-BB induced both DNA and protein synthesis. Ang II had no significant effect on the steady-state levels of cyclin-dependent kinase (CDK) inhibitor (CDKI), p27kip1, and on the activities of CDK2 and CDK4, although it caused a modest increase in cyclin E levels. In contrast, PDGF-BB induced depletion of p27kip1 and increased cyclins D1 and E levels and CDK2 and CDK4 activities. Reflecting its lack of effect on CDK activities, Ang II failed to phosphorylate tumor suppressor retinoblastoma protein, Rb. PDGF-BB, on the other hand, induced phosphorylation of Rb, consistent with its ability to activate CDKs. Together, these findings suggest that Ang II-induced hypertrophy may be due to its failure to activate cellular signaling events required for G1/S transition.
Rao
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Division of Cardiology, University of Texas Medical Branch, Galveston 77555-1064, USA. grao@utmb.edu
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000077214:Becaplermin; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects; D006965:Hyperplasia; D006984:Hypertrophy; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins