Ablation of the CDK inhibitor p57(Kip2) results in increased apoptosis and delayed differentiation during mouse development
Ablation of the CDK inhibitor p57(Kip2) results in increased apoptosis and delayed differentiation during mouse development
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DOI：
10.1101/gad.11.8.973
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发表时间：
1997-04-15
影响因子：
10.5
通讯作者：
Barbacid, M
中科院分区：
文献类型：
--
作者：
Yan, Y;Frisén, J;Barbacid, M
p57（Kip 2）是一个父系印记基因，编码几种细胞周期蛋白/Cdk复合物的有效抑制剂。p57（Kip 2）主要在终末分化细胞中表达，与G（1）Cdks相关，可导致细胞周期停滞在G（1）期。为了研究p57（Kip 2）在体内的作用，我们通过在ES细胞中同源重组来消除p57（Kip 2）基因，并产生缺乏p57（Kip 2）表达的小鼠。大多数p57（Kip 2）基因敲除小鼠出生后死亡，并表现出严重的发育缺陷，具有不同程度的遗传缺陷。正如预期的那样，遗传了母系而非父系靶向等位基因的杂合小鼠表现出类似的缺陷和新生儿死亡。p57（Kip 2）突变小鼠的发育缺陷包括腭裂和胃肠道异常，从胃肠道膨胀到空肠和回肠缺失。这些组织在p57（Kip 2）不存在的情况下显示凋亡细胞的显著增加。大多数p57（Kip 2）突变小鼠具有短肢，这是归因于软骨细胞分化期间延迟的细胞周期退出引起的异常软骨内骨化的缺陷。在缺乏p107和p130的小鼠中也观察到类似的缺陷，因此表明p57（Kip 2）可能是这些Rb相关蛋白的上游调节因子。p57（Kip 2）基因座与Beckwith-Wiedemann综合征和散发性肾母细胞瘤和肺癌的发生有关。迄今为止，我们甚至在存活>5月龄的g57（Kip 2）突变小鼠中也没有观察到肿瘤发展。这些发现表明，p57（Kip 2）在小鼠发育过程中具有重要作用，不能被其他Cdk抑制剂所补偿。
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 G(1) 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 g57(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.