title: Angiotensin II activation of cyclin D1-dependent kinase activity.
abstract: 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.
authors.affiliation: Department of Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: G
authors.initials: G
authors.lastname: Watanabe
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.forename: C
authors.initials: C
authors.lastname: Albanese
authors.forename: W E
authors.initials: WE
authors.lastname: Rainey
authors.forename: D
authors.initials: D
authors.lastname: Batlle
authors.forename: R G
authors.initials: RG
authors.lastname: Pestell
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014981:Xenopus
chemical_list: D016213:Cyclins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D000804:Angiotensin II; D019938:Cyclin D1; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018844:Cyclin-Dependent Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)