Hypoxia inhibits G1/S transition through regulation of p27 expression

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.