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Molecular and Cellular Biology, May 2004, p. 3918-3927, Vol. 24, No. 9
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.9.3918-3927.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of the Hypoxia-Inducible Factor 1{alpha}-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

Mi-Jung Lee,1 Jee-Youn Kim,1 Kyoungho Suk,2 and Jae-Hoon Park1*

Department of Pathology and Medical Research Center for Reactive Oxygen Species, College of Medicine, Kyung Hee University, Seoul 130-701,1 Department of Pharmacology, School of Medicine, Kyungpook National University, Taegu 700-422, Korea2

Received 5 September 2003/ Returned for modification 8 October 2003/ Accepted 10 February 2004

Hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) controls the cellular responses to hypoxia, activating transcription of a range of genes involved in adaptive processes such as increasing glycolysis and promoting angiogenesis. However, paradoxically, HIF-1{alpha} also participates in hypoxic cell death. Several gene products, such as BNip3, RTP801, and Noxa, were identified as HIF-1{alpha}-responsive proapoptotic proteins, but the complicated hypoxic cell death pathways could not be completely explained by the few known genes. Moreover, molecules linking the proapoptotic signals of HIF-1{alpha} directly to mitochondrial permeability transition are missing. In this work, we report the identification of an HIF-1{alpha}-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1{alpha} through a hypoxia-responsive element on the HGTD-P promoter region. When overexpressed, HGTD-P was localized to mitochondria and facilitated apoptotic cell death via typical mitochondrial apoptotic cascades, including permeability transition, cytochrome c release, and caspase 9 activation. In the process of permeability transition induction, the death-inducing domain of HGTD-P physically interacted with the voltage-dependent anion channel. In addition, suppression of HGTD-P expression by small interfering RNA or antisense oligonucleotides protected against hypoxic cell death. Taken together, our data indicate that HGTD-P is a new HIF-1{alpha}-responsive proapoptotic molecule that activates mitochondrial apoptotic cascades.

* Corresponding author. Mailing address: Department of Pathology, College of Medicine, Kyung Hee University, #1 Hoegi-dong, Dongdaemoon-Koo, Seoul 130-701, Korea. Phone: 82-2-961-0302. Fax: 82-2-960-2871. E-mail: jhpark{at}khu.ac.kr.

Molecular and Cellular Biology, May 2004, p. 3918-3927, Vol. 24, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.9.3918-3927.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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