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J. Biol. Chem., Vol. 282, Issue 19, 14073-14082, May 11, 2007

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Transcriptional Up-regulation of Inhibitory PAS Domain Protein Gene Expression by Hypoxia-inducible Factor 1 (HIF-1)

A NEGATIVE FEEDBACK REGULATORY CIRCUIT IN HIF-1-MEDIATED SIGNALING IN HYPOXIC CELLS^*

Yuichi Makino^¶1, Rie Uenishi^¶, Kensaku Okamoto, Tsubasa Isoe, Osamu Hosono, Hirotoshi Tanaka, Arvydas Kanopka^||, Lorenz Poellinger^**, Masakazu Haneda, and Chikao Morimoto

From the Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan, the Section of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical College, 2-1 Midorigaoka-higashi, Asahikawa, 078-8510, Japan, ^¶PRESTO, Japan Science and Technology Agency, 4-1-8 Honchou, Kawaguchi, Saitama 332-0012, Japan, and the ^||Institute of Biotechnology, Graiciuno 8, 2028 Vilnius, Lithuania and the ^**Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden

The inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS), a dominant negative regulator of hypoxia-inducible transcription factors (HIFs), is potentially implicated in negative regulation of angiogenesis in such tissues as the avascular cornea of the eye. We have previously shown IPAS mRNA expression is up-regulated in hypoxic tissues, which at least in part involves hypoxia-dependent alternative splicing of the transcripts from the IPAS/HIF-3 locus. In the present study, we demonstrate that a hypoxia-driven transcriptional mechanism also plays a role in augmentation of IPAS gene expression. Isolation and analyses of the promoter region flanking to the first exon of IPAS gene revealed a functional hypoxia response element at position –834 to –799, whereas the sequence upstream of the HIF-3 first exon scarcely responded to hypoxic stimuli. A transient transfection experiment demonstrated that HIF-1 mediates IPAS promoter activation via the functional hypoxia response element under hypoxic conditions and that a constitutively active form of HIF-1 is sufficient for induction of the promoter in normoxic cells. Moreover, chromatin immunoprecipitation and electrophoretic mobility shift assays showed binding of the HIF-1 complex to the element in a hypoxia-dependent manner. Taken together, HIF-1 directly up-regulates IPAS gene expression through a mechanism distinct from RNA splicing, providing a further level of negative feedback gene regulation in adaptive responses to hypoxic/ischemic conditions.

Received for publication, January 25, 2007 , and in revised form, March 12, 2007.

^* This work was supported by Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology (to Y. M. and C. M.) and from PRESTO, the Japan Science and Technology Agency (To Y. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Section of Metabolism and Biosystemic Science, Dept. of Internal Medicine, Asahikawa Medical College, 2-1 Midorigaoka-higashi, Asahikawa 078-8510, Japan. Tel.: 81-166-68-2454; Fax: 81-166-68-2459; E-mail: makino{at}asahikawa-med.ac.jp.

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