Altered expression of cell cycle proteins and prolonged duration of cardiac myocyte hyperplasia in p27KIP1 knockout mice.
-The precise role of cell cycle-dependent molecules in controlling the switch from cardiac myocyte hyperplasia to hypertrophy remains to be determined. We report that loss of p27(KIP1) in the mouse results in a significant increase in heart size and in the total number of cardiac myocytes. In comparison to p27(KIP1)+/+ myocytes, the percentage of neonatal p27(KIP1)-/- myocytes in S phase was increased significantly, concomitant with a significant decrease in the percentage of G(0)/G(1) cells. The expressions of proliferating cell nuclear antigen, G(1)/S and G(2)/M phase-acting cyclins, and cyclin-dependent kinases (CDKs) were upregulated significantly in ventricular tissue obtained from early neonatal p27(KIP1)-/- mice, concomitant with a substantial decrease in the expressions of G(1) phase-acting cyclins and CDKs. Furthermore, mRNA expressions of the embryonic genes atrial natriuretic factor and alpha-skeletal actin were detectable at significant levels in neonatal and adult p27(KIP1)-/- mouse hearts but were undetectable in p27(KIP1)+/+ hearts. In addition, loss of p27(KIP1) was not compensated for by the upregulation of other CDK inhibitors. Thus, the loss of p27(KIP1) results in prolonged proliferation of the mouse cardiac myocyte and perturbation of myocyte hypertrophy.
Cardiovascular Cellular and Molecular Biology, The Rayne Institute, St. Thomas' Hospital, London, UK.
R A
RA
Poolman
J M
JM
Li
B
B
Durand
G
G
Brooks
D016475:3T3 Cells; D000199:Actins / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics; D015415:Biomarkers; D016203:CDC2 Protein Kinase / Q000235:genetics; D042846:CDC2-CDC28 Kinases; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins
D000199:Actins; D015415:Biomarkers; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009320:Atrial Natriuretic Factor; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases