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Checkpoint Kinase 1 Prevents Cell Cycle Exit Linked to Terminal Cell Differentiation

机译：Checkpoint激酶1防止细胞周期退出与终末细胞分化相关

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Trophoblast stem (TS) cells proliferate in the presence of fibroblast growth factor 4, but in its absence, they differentiate into polyploid trophoblast giant (TG) cells that remain viable but nonproliferative. Differentiation is coincident with expression of the cyclin-dependent kinase (CDK)-specific inhibitors p21 and p57, of which p57 is essential for switching from mitotic cell cycles to endocycles. Here, we show that, in the absence of induced DNA damage, checkpoint kinase-1 (CHK1), an enzyme essential for preventing mitosis in response to DNA damage, functions as a mitogen-dependent protein kinase that prevents premature differentiation of TS cells into TG cells by suppressing expression of p21 and p57, but not p27, the CDK inhibitor that regulates mitotic cell cycles. CHK1 phosphorylates p21 and p57 proteins at specific sites, thereby targeting them for degradation by the 26S proteasome. TG cells lack CHK1, and restoring CHK1 activity in TG cells suppresses expression of p57 and restores mitosis. Thus, CHK1 is part of a “G2 restriction point” that prevents premature cell cycle exit in cells programmed for terminal differentiation, a role that CHK2 cannot play.
机译：在存在成纤维细胞生长因子4的情况下，滋养层干细胞（TS）增殖，但在不存在滋养层干细胞的情况下，它们分化为多倍体滋养层巨细胞（TG），它们仍能存活，但不增殖。分化与细胞周期蛋白依赖性激酶（CDK）特异性抑制剂p21和p57的表达相吻合，其中p57对于从有丝分裂细胞周期转换为内循环至关重要。在这里，我们表明，在没有诱导的DNA损伤的情况下，关卡激酶1（CHK1）是一种防止有丝分裂依赖于DNA损伤的必需酶，它是一种有丝分裂原依赖性蛋白激酶，可防止TS细胞过早分化为TG细胞通过抑制p21和p57的表达而抑制p27（调节有丝分裂细胞周期的CDK抑制剂）的表达。 CHK1在特定位点磷酸化p21和p57蛋白，从而将其靶向26S蛋白酶体降解。 TG细胞缺少CHK1，恢复TG细胞中的CHK1活性可抑制p57的表达并恢复有丝分裂。因此，CHK1是“ G2限制点”的一部分，可防止在编程用于终末分化的细胞中过早的细胞周期退出，这是CHK2无法发挥的作用。

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