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Reports

Hypoxic Suppression of the Cell Cycle Gene CDC25A in Tumor Cells

Stefanie Hammer, Kenneth K.-W. To, Young-Gun Yoo, Minori Koshiji and L. Eric Huang

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Hypoxia, a key microenvironmental factor for tumor development, not only stimulates angiogenesis and glycolysis for tumor expansion, but also induces cell cycle arrest and genetic instability for tumor progression. Several independent studies have shown hypoxic blockade of cell cycle progression at the G₁/S transition, arising from the inactivation of S-phase promoting cyclin E–CDK2 kinase complex. Despite these findings, the biochemical pathways leading to the cell-cycle arrest remain poorly defined. We recently showed that hypoxic activates the expression of CDNK1A encoding the CDK2 inhibitor p21^Cip1 through a novel HIF-1α–Myc pathway that involves Myc displacement from the CDNK1A promoter by the hypoxia-inducible transcription factor HIF-1α. In pursuit of further understanding of the hypoxic effects on cell cycle in tumor cells, here we report that hypoxia inhibits the expression of CDC25A, another cell cycle gene encoding a tyrosine phosphatase that maintains CDK2 activity. In accordance with the HIF-1α–Myc pathway, hypoxia requires HIF-1α for CDC25A repression, resulting in a selective displacement of an activating Myc from the CDC25A promoter that lacks a canonical E-box without affecting Myc binding in the intron. Intriguingly, HIF-1α alone fails to recapitulate the hypoxic effect, indicating that HIF-1α is necessary but insufficient for the hypoxic repression. Taken together, our studies support that hypoxia inhibits cell cycle progression by controlling the expression of various cell cycle genes.

Authors

Stefanie Hammer

National Cancer Institute, NIH; Bethesda MD USA and Schering AG; Berlin, Germany

Kenneth K.-W. To

National Cancer Institute, NIH; Bethesda MD USA

Young-Gun Yoo

University of Utah School of Medicine; Salt Lake City, Utah

Minori Koshiji

National Cancer Institute; NIH, Bethesda, MD USA and Banyu Pharmaceutical Co, Tokyo, Japan

L. Eric Huang

National Cancer Institute; NIH, Bethesda, MD USA and University of Utah School of Medicine; Salt Lake City, UT USA

Purchase article for $19

Subscribe to this journal for $129/year