ANGIOTENSIN-II ACTIVATION OF CYCLIN D1-DEPENDENT KINASE-ACTIVITY

Angiotensin II (AII) binds to specific G protein-coupled receptors and is mitogenic in adrenal, liver epithelial, and vascular smooth muscle cells. Since the cyclin D1 gene encodes the regulatory subunit of the cyclin D1-dependent kinase (CD1K) required for phosphorylation of the retinoblastoma protein (pRB), an essential and rate-limiting step in G(1) phase progression of the cell cycle, we examined the effect of AI I. on cyclin D1 expression and CD1K activity in the human adrenal cell line H295R. AII (10(-6) M) stimulated G(1) phase progression within 1 2 h, with a maximal effect after 72 h. This action was antedated by th e induction of cyclin D1 mRNA (3-fold), cyclin D1 nuclear protein abun dance (4-fold), and CD1K activity (4-fold). AT(1) induced cyclin D1 pr omoter activity 4-fold, via the AT(1) receptor through an enhancer seq uence at -954 base pairs. c-Fos and c-Jun bound the cyclin D1 -954 enh ancer sequence, and the abundance of c-Fos within this complex was inc reased by All treatment, AII induced extracellular signal-regulated ki nase (ERK) activity 7-fold, and dominant-negative mutants of either p2 1(ras) or ERK reduced AII stimulated cyclin D1 promoter activity. Thes e findings suggest that AII may stimulate mitogenesis by increasing CD 1K activity through a p21(ras)/ERK/activator protein 1 pathway.