Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development.
p57(Kip2) is a paternally imprinted gene that encodes a potent inhibitor of several cyclin/Cdk complexes. p57(Kip2) is primarily expressed in terminally differentiated cells, associates with G1 Cdks, and can cause cell cycle arrest in G1 phase. To investigate the role of p57(Kip2) in vivo, we have ablated the p57(Kip2) gene by homologous recombination in ES cells and generated mice devoid of p57(Kip2) expression. Most p57(Kip2) null mice die after birth and display severe developmental defects with varying degrees of penetrance. As expected, heterozygous mice that inherit a maternal, but not a paternal, targeted allele exhibit similar deficiencies and neonatal death. Developmental defects of p57(Kip2) mutant mice include cleft palate and gastrointestinal abnormalities ranging from an inflated GI tract to loss of the jejunum and ileum. These tissues display a significant increase of apoptotic cells in the absence of p57(Kip2). Most p57(Kip2) mutant mice have short limbs, a defect attributable to abnormal endochondral ossification caused by delayed cell cycle exit during chondrocyte differentiation. A similar defect has been observed in mice lacking p107 and p130, thus suggesting that p57(Kip2) might be an upstream regulator of these Rb-related proteins. The p57(Kip2) locus has been implicated in the Beckwith-Wiedemann syndrome and in the development of sporadic Wilms' tumors and lung carcinomas. To date, we have not observed neoplastic development even in those p57(Kip2) mutant mice that have survived for >5 months of age. These findings indicate that p57(Kip2) has an important role during mouse development that cannot be compensated by other Cdk inhibitors.
Yan
Y
Y
Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Frisén
J
J
Lee
M H
MH
Massagué
J
J
Barbacid
M
M
D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002356:Cartilage / Q000196:embryology / Q000473:pathology; D002454:Cell Differentiation; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics; D003433:Crosses, Genetic; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005314:Embryonic and Fetal Development / Q000235:genetics*; D004791:Enzyme Inhibitors; D005260:Female; D007422:Intestines / Q000002:abnormalities / Q000196:embryology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D009928:Organ Specificity; D010012:Osteogenesis; D013270:Stomach / Q000002:abnormalities / Q000196:embryology
C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D018844:Cyclin-Dependent Kinases