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 cell-cycle 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% O(2)) 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.
Highlights
Hypoxia is a stress that causes alterations in signal transduction and gene instability
Because cyclin D1 has the key role in regulating the G1/S transition and mediating the response to other growth factors, we examined the effect of DFO or hypoxia on cyclin D1 protein levels
The expression of cyclin D1 was increased by treatment with DFO or hypoxia via dose and time dependent manner in HC11 and MCF-7 cells, a maximum increase was seen after 6 h of DFO or hypoxia stimulation (Figure 2)
Summary
Hypoxia is a stress that causes alterations in signal transduction and gene instability. Hypoxia plays a significant role in forming a tumor phenotype and tumor progression (Bando et al, 2003). Hypoxia results in adaptive changes in the transcription of a wide range of genes involved either in increasing the availability of oxygen to the tissues or in decreasing the cellular consumption of oxygen by activating glycolysis (BrahimiHorn et al, 2001). Most solid tumors contain hypoxic components (Harris, 2002). Recent reports revealed that the status of hypoxia in tumor tissue is a marker of poor prognosis in several types of solid cancers, including breast cancer (Schindl et al, 2002).
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