Exp Mol Med.
2005 Aug;37(4):353-364.
Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells
- Affiliations
-
- 1Department of Pathology, College of Medicine and Bio-Food and Drug Research Center, Konkuk University, Chungju 380-701, Korea. ymyang@kku.ac.kr
- 2Bio-Food and Drug Research Center, Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungju 380-701, Korea.
- 3Oral and Pharyngeal Cancer Branch, NIDCR, NIH, Bethesda, MD 20892-4340, USA.
- 4Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 5Laboratory of Kidney and Electrolyte Metabolism, NHLBI, NIH, Bethesda, MD 20892-1603, USA.
- 6Department of Animal Biotechnology, College of Animal Husbandry, Konkuk University, Seoul 143-701, Korea.
- 7Department of Applied Biology and Chemistry, Konkuk University, Seoul 143-701, Korea.
- 8Natural F&P Corp. O-Chang Science Industry Plaza, Chongwon 363-883, Korea.
Abstract
- Hypoxia, a common consequence of solid tumor growth in breast cancer or other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cellcycle control proteins. As we have shown previously, hypoxia activates STAT5 (signal transducer and activator of transcription 5) and increases its binding activity to the GAS element in mammary epithelial cells. In this study we attempted to elucidate the mechanism by which cyclin D1 is regulated by the STAT5 protein under hypoxic conditions. Our data demonstrate that hypoxia (2% O2) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11). Imunoprecipitation and subsequent Western analysis showed that Jak2 leads to the tyrosine phosphorylation and activation of STAT5a or STAT5b under hypoxic conditions. Using a transfected COS-7 cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increased under hypoxic conditions or DFO treatment. The activity of the STAT5b/cyclin D1 promoter increased significantly by 12 h of hypoxia, whereas the activity of the STAT5a/cyclin D1 promoter was unaffected under hypoxic conditions. These increases in promoter activity are predominantly mediated by the Jak2/ STAT5b signaling pathway. We have shown by EMSA that hypoxia induces STAT5 to bind to the cyclin D1 promoter (GAS-1) in MCF-7 and HC11 cells. These data suggest that STAT5b may mediate the transcriptional activation of cyclin D1 after hypoxic stimulation.
MeSH Terms
-
Anaerobiosis/genetics
Animals
Breast Neoplasms/*genetics/metabolism
COS Cells
Cell Hypoxia/genetics
Cercopithecus aethiops
Cyclin D1/*genetics
Deferoxamine/pharmacology
Female
*Gene Expression Regulation, Neoplastic
Humans
Phosphorylation/drug effects
Promoter Regions (Genetics)
Protein-Tyrosine Kinase/*metabolism
Proto-Oncogene Proteins/*metabolism
Research Support, Non-U.S. Gov't
Serine/metabolism
Tumor Cells, Cultured
Tyrosine/metabolism
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