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DNA Damage Is a Prerequisite for p53-Mediated Proteasomal Degradation of HIF-1 in Hypoxic Cells and Downregulation of the Hypoxia Marker Carbonic Anhydrase IX

Milota Kaluzová,^1,2, Stefan Kaluz,^1,2, Michael I. Lerman,³ and Eric J. Stanbridge^1*

Department of Microbiology and Molecular Genetics, College of Medicine, University of California at Irvine, Irvine, California 92717,¹ Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic,² and Laboratory of Immunobiology, National Cancer Institute at Frederick, Frederick, Maryland 21701³

Received 9 December 2003/ Returned for modification 3 February 2004/ Accepted 8 April 2004

We investigated the relationship between the tumor suppressor p53 and the hypoxia-inducible factor-1 (HIF-1)-dependent expression of the hypoxia marker, carbonic anhydrase IX (CAIX). MCF-7 (wt p53) and Saos-2 (p53-null) cells displayed similar induction of CAIX expression and CA9 promoter activity under hypoxic conditions. Activation of p53 by the DNA damaging agent mitomycin C (MC) was accompanied by a potent repression of CAIX expression and the CA9 promoter in MCF-7 but not in Saos-2 cells. The activated p53 mediated increased proteasomal degradation of HIF-1 protein, resulting in considerably lower steady-state levels of HIF-1 protein in hypoxic MCF-7 cells but not in Saos-2 cells. Overexpression of HIF-1 relieved the MC-induced repression in MCF-7 cells, confirming regulation at the HIF-1 level. Similarly, CA9 promoter activity was downregulated by MC in HCT 116 p53^+/+ but not the isogenic p53^–/– cells. Activated p53 decreased HIF-1 protein levels by accelerated proteasome-dependent degradation without affecting significantly HIF-1 transcription. In summary, our results demonstrate that the presence of wtp53 under hypoxic conditions has an insignificant effect on the stabilization of HIF-1 protein and HIF-1-dependent expression of CAIX. However, upon activation by DNA damage, wt p53 mediates an accelerated degradation of HIF-1 protein, resulting in reduced activation of CA9 transcription and, correspondingly, decreased levels of CAIX protein. A model outlining the quantitative relationship between p53, HIF-1, and CAIX is presented.

M.K. and S.K. contributed equally to this work.

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