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Molecular and Cellular Biology, July 2004, p. 5757-5766, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5757-5766.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Milota Kaluzová,1,2,{dagger} Stefan Kaluz,1,2,{dagger} Michael I. Lerman,3 and Eric J. Stanbridge1*

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{alpha} protein, resulting in considerably lower steady-state levels of HIF-1{alpha} protein in hypoxic MCF-7 cells but not in Saos-2 cells. Overexpression of HIF-1{alpha} relieved the MC-induced repression in MCF-7 cells, confirming regulation at the HIF-1{alpha} level. Similarly, CA9 promoter activity was downregulated by MC in HCT 116 p53+/+ but not the isogenic p53–/– cells. Activated p53 decreased HIF-1{alpha} protein levels by accelerated proteasome-dependent degradation without affecting significantly HIF-1{alpha} transcription. In summary, our results demonstrate that the presence of wtp53 under hypoxic conditions has an insignificant effect on the stabilization of HIF-1{alpha} protein and HIF-1-dependent expression of CAIX. However, upon activation by DNA damage, wt p53 mediates an accelerated degradation of HIF-1{alpha} 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{alpha}, and CAIX is presented.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Medical Science I B210, University of California at Irvine, College of Medicine, Irvine, CA 92697-4025. Phone: (949) 824-7024. Fax: (949) 824-8598. E-mail: ejstanbr{at}uci.edu.

{dagger} M.K. and S.K. contributed equally to this work.

Molecular and Cellular Biology, July 2004, p. 5757-5766, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5757-5766.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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