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Cancer Res. 2003 Mar 1;63(5):917-22.

Expression of the hypoxia marker carbonic anhydrase IX is critically dependent on SP1 activity. Identification of a novel type of hypoxia-responsive enhancer.

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  • 1Department of Microbiology and Molecular Genetics, College of Medicine, University of California at Irvine, California 92717, USA.


In the present study, we further studied mechanisms of transcriptional regulation of the tumor-associated carbonic anhydrase IX (CAIX). We identified PR5 in the CA9 promoter as another SP1/SP3-binding site. As shown by electromobility shift assays and block-replacement mutagenesis, PR5 is functionally equivalent to the SP1/SP3-binding PR1 identified previously. However, there is a strong requirement for SP1/SP3 activity in the PR1 position, and SP1/SP3 activity from the PR5 position cannot compensate for this. In various cell lines, the expression of endogenous CAIX and activity of CA9 promoter constructs depend on SP1/SP3 activity as demonstrated by the dose-dependent inhibitory effect of the SP1 inhibitor mithramycin A. The two conditions of the induction of CAIX expression described previously differ in their sensitivity to mithramycin A inhibition; the hypoxia-mimic-induced expression is less sensitive than the cell density (mild hypoxia)-induced expression. Our present study highlights the importance of SP1/SP3 activity for CAIX expression and provides additional evidence for distinct mechanisms responsible for true and mild hypoxia-induced CAIX expression. The presence of a SP1/SP3-binding element in the PR1 position is absolutely required for mild hypoxia-induced activity, and it significantly up-regulates the true hypoxic induction. The SP1/SP3 and hypoxia-response element in the CA9 promoter thus may represent a novel type of enhancer capable of mounting responses to a wider range of hypoxic conditions.

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