Hypoxia inhibits G1/S transition through regulation of p27 expression
Hypoxia inhibits G1/S transition through regulation of p27 expression
复制标题
DOI：
10.1074/jbc.m010189200
复制
发表时间：
2001-03-16
影响因子：
4.8
通讯作者：
Dang, CV
中科院分区：
文献类型：
--
作者：
Gardner, LB;Li, Q;Dang, CV
哺乳动物细胞对低氧的反应包括适应性代谢变化和G(1)期细胞周期停滞。虽然低氧诱导转录因子(HIF-1)对代谢基因的转录调控已被证实，但低氧诱导G(1)期停滞的机制尚不清楚。通过使用基因定义的原代野生型小鼠胚胎成纤维细胞和对G(1)/S检查点调控无效的细胞，我们观察到视网膜母细胞瘤蛋白是G(1)/S低氧诱导检查点所必需的，而p53和p21不是必需的。此外，我们还发现低氧诱导细胞周期蛋白依赖性激酶抑制因子p27的表达，从而抑制CDK2的活性，并通过视网膜母细胞瘤蛋白的低磷酸化、p27的减少或缺失来阻止细胞进入S时相，从而取消了低氧诱导的G(1)检查点，提示它是低氧细胞G(1)/S转换的关键调节因子。有趣的是，低氧诱导p27似乎是转录的，并且通过其近端启动子的不依赖于HIF-1的区域，这一关于低氧诱导G(1)/S调控的分子机制的论证为哺乳动物细胞对低氧压的基本反应提供了洞察。
Mammalian cellular responses to hypoxia include adaptive metabolic changes and a G(1) cell cycle arrest. Although transcriptional regulation of metabolic genes by the hypoxia-induced transcription factor (HIF-1) has been established, the mechanism for the hypoxia-induced G(1) arrest is not known. By using genetically defined primary wild-type murine embryo fibroblasts and those nullizygous for regulators of the G(1)/S checkpoint, we observed that the retinoblastoma protein is essential for the G(1)/S hypoxia-induced checkpoint, whereas p53 and p21 are not required. In addition, we found that the cyclin-dependent kinase inhibitor p27 is induced by hypoxia, thereby inhibiting CDK2 activity and forestalling S phase entry through retinoblastoma protein hypophosphorylation, Reduction or absence of p27 abrogated the hypoxia-induced G(1) checkpoint, suggesting that it is a key regulator of G(1)/S transition in hypoxic cells. Intriguingly, hypoxic induction of p27 appears to be transcriptional and through an HIF-1-independent region of its proximal promoter, This demonstration of the molecular mechanism of hypoxia-induced G(1)/S regulation provides insight into a fundamental response of mammalian cells to low oxygen tension.