title: C-reactive protein induces p53-mediated cell cycle arrest in H9c2 cardiac myocytes.
abstract: C-reactive protein (CRP) is one of the most important biomarker for cardiovascular diseases. Recent studies have shown that CRP affects cell survival, differentiation and apoptosis. However, the effect of CRP on the cell cycle has not been studied yet. We investigated the cell cycle alterations and cellular mechanisms induced by CRP in H9c2 cardiac myocytes. Flow cytometry analysis showed that CRP-treated H9c2 cells displayed cell cycle arrest in G0/G1 phase. CRP treatment resulted in a significant reduction in the levels of CDK4, CDK6 and cyclin D1 in a concentration-dependent manner. Interestingly, CRP caused an increase in the p53 accumulation and its phosphorylation on Ser15, leading to induce p21 upregulation. Treatment with a specific p53 inhibitor, PFT-α restored the levels of CDK4 and CDK6. A significant increase of ERK1/2 phosphorylation level was detected in CRP-treated cells. Furthermore, pretreatment of a specific ERK inhibitor resulted in decreased p53 phosphorylation and p21 induction. ERK inhibitor pretreatment induced significant restoration of protein levels of CDK4 and CDK6, leading to re-entry into the cell cycle. In addition, increased phosphorylation of p53 and ERK induced by CRP was considerably reversed by Fc gamma receptor IIIa (FcγRIIIa) knock-down using siRNA. FcγRIIIa siRNA transfection also restored the levels of cell cycle proteins. Our study has provided the first proposal on the novel insights into how CRP directly affects cell cycle in cells.
authors.affiliation: Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Choi
authors.forename: Kyung Hye
authors.initials: KH
authors.lastname: Lee
authors.forename: Soo Hyuk
authors.initials: SH
authors.lastname: Kim
authors.forename: Taewon
authors.initials: T
authors.lastname: Jin
authors.forename: Beom Seob
authors.initials: BS
authors.lastname: Lee
authors.forename: Jaewon
authors.initials: J
authors.lastname: Oh
authors.forename: Ho-Yeon
authors.initials: HY
authors.lastname: Won
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Seok-Min
authors.initials: SM
authors.lastname: Kang
authors.forename: Ji Hyung
authors.initials: JH
authors.lastname: Chung
mesh_terms: D002097:C-Reactive Protein / Q000494:pharmacology / Q000502:physiology*; D002453:Cell Cycle; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C080568:Fc gamma receptor IIA; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D012694:Serine; D002097:C-Reactive Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3