Hypoxia Inhibits G1/S Transition through Regulation of p27 Expression

Mammalian cellular responses to hypoxia include adaptive metabolic changes and a G1 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 G1 arrest is not known. By usi...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-03, Vol.276 (11), p.7919-7926
Main Authors: Gardner, Lawrence B., Li, Qing, Park, Michele S., Flanagan, W.Michael, Semenza, Gregg L., Dang, Chi V.
Format: Article
Language:English
Subjects:
Animals
CDC2-CDC28 Kinases
Cell Cycle Proteins
Cell Hypoxia
Cells, Cultured
Cyclin D
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases - metabolism
Cyclins - metabolism
DNA-Binding Proteins - physiology
G1 Phase
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Microtubule-Associated Proteins - genetics
Microtubule-Associated Proteins - physiology
Nuclear Proteins - physiology
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases - metabolism
Rats
S Phase
Transcription Factors
Tumor Suppressor Proteins
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Summary:Mammalian cellular responses to hypoxia include adaptive metabolic changes and a G1 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 G1 arrest is not known. By using genetically defined primary wild-type murine embryo fibroblasts and those nullizygous for regulators of the G1/S checkpoint, we observed that the retinoblastoma protein is essential for the G1/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 G1 checkpoint, suggesting that it is a key regulator of G1/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 G1/S regulation provides insight into a fundamental response of mammalian cells to low oxygen tension.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M010189200