Differential regulation of p27(Kip1) expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms

Platelet-derived growth factor-BE (PDGF-BB) acts as a full mitogen for cult ured aortic smooth muscle cells (SMC), promoting DNA synthesis and cell pro liferation. In contrast, angiotensin II (Ang II) in duces cellular hypertro phy as a result of increased protein synthesis, but is unable to drive cell s into S phase. In an effort to understand the molecular basis for this dif ferential 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) cy clins 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 s timulated 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 st imulate phosphorylation of the enzyme on threonine and to downregulate p27( Kip1) expression. By contrast, exposure to PDGF-BB resulted in a progressiv e 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 a n 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 accum ulation. We also show that the failure of Ang II to promote S phase entry i s not related to the autocrine production of transforming growth factor-bet a 1 by aortic SMC. These results identify p27(Kip1) as an important regulat or of the phenotypic response of vascular SMC to mitogenic and hypertrophic stimuli.