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Upregulation of transcription factor HIF-1α in hypoxic or growth factor stimulated normoxic human tumor cells has been associated with increased cell survival and resistance to apoptosis in human cancer. We found that HIF-1α activates expression of an inhibitor of apoptosis protein gene, survivin, selectively in tumor cells. This mechanism may be critical for the survival of hypoxic tumor cells as well as the progression of breast cancer since co-localization of high levels of HIF-1α and survivin is found in human ductal carcinoma in situ tissues but not in normal breast tissues. Examination of transcriptional factors regulating survivin gene expression reveals a novel mechanism for the HIF-1α activated gene expression. Unlike the activation of many other genes that are mediated by the binding of HIF-1α to the hypoxia responsive element (HRE) and then interacting with p300/CBP, the expression of survivin gene requires the interactions of HIF-1α first to Sp-1 located about 20 nt upstream of the HRE site. The binding of HIF-1α to Sp1 activates survivin gene transcription through interaction with the TBP family of proteins. However, another HIF-1α binds to the HRE on the survivin promoter and then recruits several inhibitory transcriptional factors, such as p53 and HDCA6, to negatively regulate survivin gene expression. It is likely that changes in the balance of those positive and negative transcriptional factors control the expression of survivin gene specifically in human cancer cells. Identification of the cellular factors that are critical for activation of survivin gene expression should provide new molecular targets for the development of novel therapeutic approaches for the treatment of cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA