Ablation of the CDK inhibitor p57Kip2 results in increased apoptosis and delayed differentiation during mouse development.

Abstract

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 G 1 Cdks, and can cause cell cycle arrest in G1 phase. To investigate the role of p57 Kip2 in vivo, we have ablated the p57 rap2 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 ~'2 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 ~:ip2 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 mp2 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.

The cell cycle inhibitor p57Kip2 promotes cell death via the mitochondrial apoptotic pathway

“…Although p57 Kip2 -null mutant mice exhibit an increase in the rate of cell death in several cell populations during embryogenesis, [4][5][6][7] whether this increased apoptosis is a direct or indirect effect due to aberrations in cell proliferation and differentiation is still discussed. For example, it seems that in the p57 Kip2 -deficient retina, apoptosis precisely compensates for the inappropriate proliferation to preserve the correct proportion of the major retinal cell types.…”

“…p57 Kip2 -null mutant mice display severe developmental defects. [4][5][6][7] Interestingly, many of the defects described are not directly linked to increased cell proliferation. 4,5,7 In addition, p57 Kip2 has been shown to influence cell differentiation of several cell types, implying that p57 Kip2 may have a broader scope of cellular action than only being a cell cycle inhibitor.…”

“…[4][5][6][7] Interestingly, many of the defects described are not directly linked to increased cell proliferation. 4,5,7 In addition, p57 Kip2 has been shown to influence cell differentiation of several cell types, implying that p57 Kip2 may have a broader scope of cellular action than only being a cell cycle inhibitor. [5][6][7] We and others have shown that p57 Kip2 -deficient mice exhibit an increase in the rate of cell death in several cell populations during embryogenesis.…”

“…[5][6][7] We and others have shown that p57 Kip2 -deficient mice exhibit an increase in the rate of cell death in several cell populations during embryogenesis. 4,6,7 Whether this increased apoptosis is a direct or indirect effect due to aberrations in cell proliferation and differentiation is not known. Importantly, the p57 Kip2 gene, located on chromosome 11p15.5, has been suggested to be a tumor suppressor gene, being inactivated in various types of human cancers.…”

p27Kip1 induces drug resistance by preventing apoptosis upstream of cytochrome c release and procaspase-3 activation in leukemic cells

“…The negative e ect of p21 Waf1/Cip1 on drug-induced cell death has been demonstrated both in vitro (Waldman et al, 1996;Zhang et al, 1995) and in vivo (Waldman et al, 1997). Knock-out p57 Kip2 mice have suggested a role for this CDKI as an anti-apoptotic protein (Yan et al, 1997). p27 Kip1 has been implicated as a drug resistance factor in tumor cells spheroids (St Croix et al, 1996) as well as in colon carcinoma cells grown as con¯uent monolayers .…”