title: Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy.
abstract: OBJECTIVE
  A number of stimuli induce cardiac hypertrophy and may lead to cardiomyopathy and heart failure. It is believed that cardiomyocytes withdraw from the cell cycle shortly after birth and become terminally differentiated. However, cell cycle regulatory proteins take part in the development of hypertrophy, and it is important to elucidate the mechanisms of how these proteins are involved in the hypertrophic response in cardiomyocytes.
  
  
  RESULTS
  In the present study, by immunohistochemistry with a phosphorylation-specific antibody, we found that cyclin D-cdk4/6-phosphorylated retinoblastoma protein (pRb) during hypertrophy and expression of an unphosphorylatable pRb mutant impaired hypertrophic growth in cardiomyocytes. Transcription factor E2F was activated by hypertrophic elicitors but activation was impaired by pharmacological inhibition of cyclin D-cdk4/6. Inhibition of cyclin E-cdk2 complex only partly impaired E2F activity and did not prevent hypertrophic growth, but diminished endoreplication during hypertrophy.
  
  
  CONCLUSIONS
  These results indicate that cyclin D-cdk4/6-dependent phosphorylation of pRb and activation of E2F is necessary for hypertrophic growth in cardiomyocytes, whereas cyclin E-cdk2 kinase is not necessary for hypertrophy but regulates endoreplication in these cells. The data support the notion that hypertrophic growth of cardiomyocytes involves a partial progression through the G1 phase of the cell cycle
authors.affiliation: Risø National Laboratory, Biosystems Department, Cell Biology Programme, Roskilde, Denmark. rebecca.hinrichsen@risoe.dk
authors.forename: R
authors.initials: R
authors.lastname: Hinrichsen
authors.forename: A H
authors.initials: AH
authors.lastname: Hansen
authors.forename: S
authors.initials: S
authors.lastname: Haunsø
authors.forename: P K
authors.initials: PK
authors.lastname: Busk
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D050684:E2F Transcription Factors / Q000378:metabolism; D006588:Hexanones / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000077546:Roscovitine; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D050684:E2F Transcription Factors; D006588:Hexanones; D011687:Purines; D016160:Retinoblastoma Protein; D000077546:Roscovitine; C053433:1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone; D000804:Angiotensin II; D004247:DNA; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6