Hypoxic suppression of the cell cycle gene CDC25A in tumor cells.
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 p21Cip1, through a novel HIF-1alpha-Myc pathway that involves Myc displacement from the CDNK1A promoter by the hypoxia-inducible transcription factor HIF-1alpha. 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-1alpha-Myc pathway, hypoxia requires HIF-1alpha for CDC25A repression, resulting in a selective displacement of an activating Myc from the CDC25A promoter without affecting a canonical Myc binding in the intron. Intriguingly, HIF-1alpha alone fails to recapitulate the hypoxic effect, indicating that HIF-1alpha is necessary but insufficient for the hypoxic repression. Taken together, our studies indicate that hypoxia inhibits cell cycle progression by controlling the expression of various cell cycle genes.
Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Stefanie
S
Hammer
Kenneth K-W
KK
To
Young-Gun
YG
Yoo
Minori
M
Koshiji
L Eric
LE
Huang
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism*
D018797:Cell Cycle Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases