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Hypoxic suppression of the cell cycle gene CDC25A in tumor cells
Stefanie Hammer1, Kenneth K-W To, Young-Gun Yoo
1Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Abstract:
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.
Insights
Hypoxia, or low oxygen, halts tumor cell cycle progression by inhibiting key genes like CDC25A. This involves the hypoxia-inducible factor 1-alpha (HIF-1alpha) and Myc pathway, revealing new therapeutic targets for cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Hypoxia is a critical factor in tumor development, promoting growth and progression.
- Tumor hypoxia causes cell cycle arrest at the G1/S transition, linked to cyclin E-CDK2 inactivation.
- The precise molecular mechanisms driving hypoxia-induced cell cycle arrest are not fully understood.
Purpose of the Study:
- To investigate the molecular pathways through which hypoxia affects cell cycle gene expression in tumor cells.
- To elucidate the role of HIF-1alpha and Myc in regulating CDC25A expression under hypoxic conditions.
- To further define the biochemical mechanisms underlying hypoxia-induced cell cycle arrest.
Main Methods:
- Investigated the impact of hypoxia on CDC25A gene expression in tumor cells.
- Utilized chromatin immunoprecipitation assays to study the binding of HIF-1alpha and Myc to the CDC25A promoter.
- Examined the necessity and sufficiency of HIF-1alpha in mediating hypoxic repression of CDC25A.
Main Results:
- Hypoxia inhibits the expression of CDC25A, a gene crucial for maintaining CDK2 activity.
- Hypoxia-induced repression of CDC25A requires HIF-1alpha, which selectively displaces Myc from the gene's promoter.
- HIF-1alpha alone is insufficient to cause CDC25A repression, indicating the involvement of other factors.
Conclusions:
- Hypoxia inhibits tumor cell cycle progression by regulating the expression of multiple cell cycle genes.
- The HIF-1alpha-Myc pathway plays a significant role in mediating hypoxia's effects on cell cycle regulators like CDC25A.
- These findings provide insights into the complex molecular interplay governing cell cycle control in hypoxic tumor microenvironments.
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