Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

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.

The Clinical Significance of STAT3 and STAT5 Activation in Renal Cell Carcinoma / 대한비뇨기과학회지

PURPOSE: Cytokines, hormones and growth factors use signal transducers and activators of transcription (STAT) signaling pathways to control various biological responses, including development, differentiation, cell proliferation and survival. STAT3 and 5 help promote cell cycle progression and cellular transformation and prevent apoptosis. In this research, the presence of STAT3 and STAT5 activation and their association with pathological features and clinical outcome in renal cell carcinoma cases were studied. MATERIALS AND METHODS: Using immunohistochemistry with rabbit polyclonal anti-STAT3 and STAT5 antibodies, forty-eight paraffin-embedded renal cell carcinoma specimens were examined for the activation status of STAT3 and STAT5. Cells of which 10% or more were left with a dark brown stains in the nucleus were regarded as positive tumor cells. The activation status of STAT3 and STAT5 were compared with the clinicopathological variables. RESULTS: Significant associations of STAT3 activation with tumor size, T-stage, distant metastases and low survival rate were observed (p<0.05); and in STAT5, significant associations with distant metastases and low survival rate were observed (p<0.05). CONCLUSIONS: The results of this study strongly suggest that the activation of STAT3 and STAT5 contribute to the development and progression of the renal cell carcinoma.