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Molecular and Cellular Biology, April 2002, p. 2283-2293, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2283-2293.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Identification of a Novel Hypoxia-Inducible Factor 1-Responsive Gene, RTP801, Involved in Apoptosis

Tzipora Shoshani,1 Alexander Faerman,1 Igor Mett,1 Elena Zelin,1 Tamar Tenne,1,{dagger} Svetlana Gorodin,1 Yana Moshel,1 Shlomo Elbaz,1 Andrei Budanov,2 Ayelet Chajut,1 Hagar Kalinski,1 Iris Kamer,1 Ada Rozen,1 Orna Mor,1 Eli Keshet,3 Dena Leshkowitz,1 Paz Einat,1 Rami Skaliter,1 and Elena Feinstein1*

Quark Biotech, Inc., Cleveland, Ohio 44106,1 Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607,2 Department of Molecular Biology, Hadassah Medical School, The Hebrew University, Jerusalem 91120, Israel3

Received 26 July 2001/ Returned for modification 11 October 2001/ Accepted 3 December 2001

Hypoxia is an important factor that elicits numerous physiological and pathological responses. One of the major gene expression programs triggered by hypoxia is mediated through hypoxia-responsive transcription factor hypoxia-inducible factor 1 (HIF-1). Here, we report the identification and cloning of a novel HIF-1-responsive gene, designated RTP801. Its strong up-regulation by hypoxia was detected both in vitro and in vivo in an animal model of ischemic stroke. When induced from a tetracycline-repressible promoter, RTP801 protected MCF7 and PC12 cells from hypoxia in glucose-free medium and from H2O2-triggered apoptosis via a dramatic reduction in the generation of reactive oxygen species. However, expression of RTP801 appeared toxic for nondividing neuron-like PC12 cells and increased their sensitivity to ischemic injury and oxidative stress. Liposomal delivery of RTP801 cDNA to mouse lungs also resulted in massive cell death. Thus, the biological effect of RTP801 overexpression depends on the cell context and may be either protecting or detrimental for cells under conditions of oxidative or ischemic stresses. Altogether, the data suggest a complex type of involvement of RTP801 in the pathogenesis of ischemic diseases.

* Corresponding author. Mailing address: Quark Biotech Inc./QBI Enterprises, Ltd., Weizmann Science Park, POB 4071, Ness Ziona 70400, Israel. Phone: 972-8-9305111, ext. 113. Fax: 972-8-9406476. E-mail: elenaf{at}qbi.co.il.

{dagger} Present address: Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.

Molecular and Cellular Biology, April 2002, p. 2283-2293, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2283-2293.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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