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 G₁ phase progression of the cell cycle, we examined the effect of AII on cyclin D1 expression and CD₁K activity in the human adrenal cell line H295R. AII (10^-6 M) stimulated G₁ phase progression within 12 h, with a maximal effect after 72 h. This action was antedated by the induction of cyclin D1 mRNA (3-fold), cyclin D1 nuclear protein abundance (4-fold), and CD₁K activity (4-fold). AII induced cyclin D1 promoter activity 4-fold, via the AT₁ receptor through an enhancer sequence at -954 base pairs. c-Fos and c-Jun bound the cyclin D1 -954 enhancer sequence, and the abundance of c-Fos within this complex was increased by AII treatment. AII induced extracellular signal-regulated kinase (ERK) activity 7-fold, and dominant-negative mutants of either p21(ras) or ERK reduced AII-stimulated cyclin D1 promoter activity. These findings suggest that AII may stimulate mitogenesis by increasing CD₁K activity through a p21(ras)/ERK/activator protein 1 pathway.