title: Resveratrol increases serine15-phosphorylated but transcriptionally impaired p53 and induces a reversible DNA replication block in serum-activated vascular smooth muscle cells.
abstract: Resveratrol (RV), a polyphenolic stilbene derivative, has been proposed to exert a plethora of beneficial cardiovascular effects. Of these, in particular, inhibition of vascular smooth muscle cell (VSMC) proliferation shows great promise for preventing cardiovascular disease. In the present study, we show that RV leads to a reversible arrest in early S phase of the VSMC cycle, accompanied by an accumulation of hyperphosphorylated retinoblastoma protein. In contrast to studies with other cell systems, RV decreases cellular levels of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1). This is of particular interest because phosphorylated p53 protein (serine(15)) is strongly enhanced by this substance. We further found that RV only slightly inhibits phosphorylation of Erk 1/2, protein kinase B/Akt, and p70(S6) kinase upon serum stimulation. Thus, inhibition of these kinases is not likely to contribute to the cell cycle effect of RV. Importantly, the observed S phase arrest is not linked to an increase in apoptotic cell death: there was no detectable increase in apoptotic nuclei and in levels of the proapoptotic protein Bax. This is the first study elucidating the molecular pathways mediating the antiproliferative properties of RV in VSMCs.
authors.affiliation: Department of Pharmacy, Center of Drug Research, University of Munich, Munich, Germany.
authors.forename: Ursula G B
authors.initials: UG
authors.lastname: Haider
authors.forename: Dan
authors.initials: D
authors.lastname: Sorescu
authors.forename: Kathy K
authors.initials: KK
authors.lastname: Griendling
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
mesh_terms: D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology*; D001798:Blood Proteins / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects*; D005720:Gamma Rays; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D016587:Antimutagenic Agents; D001798:Blood Proteins; C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D012694:Serine; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020928:Mitogen-Activated Protein Kinases; D000077185:Resveratrol