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Molecular and Cellular Biology, February 2001, p. 1297-1310, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1297-1310.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Regulation of p53 by Hypoxia: Dissociation of Transcriptional Repression and Apoptosis from p53-Dependent Transactivation

Constantinos Koumenis,1,dagger Rodolfo Alarcon,1 Ester Hammond,1 Patrick Sutphin,1 William Hoffman,2 Maureen Murphy,2 Jennifer Derr,1 Yoichi Taya,3 Scott W. Lowe,4 Michael Kastan,5 and Amato Giaccia1,*

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 943051; Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 191112; National Cancer Center Research Institute, Chuo-ku, Tokyo 104, Japan3; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 1172414; and Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 081055

Received 14 September 2000/Returned for modification 20 September 2000/Accepted 10 November 2000

Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.

* Corresponding author. Mailing address: Stanford University School of Medicine, CCSR-South, Room 1255, 269 Campus Drive, Stanford, CA 94305-5152. Phone: (650) 723-7366. Fax: (650) 723-7382. E-mail: giaccia{at}stanford.edu.

dagger Present address: Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157.

Molecular and Cellular Biology, February 2001, p. 1297-1310, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1297-1310.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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