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Originally published In Press as doi:10.1074/jbc.C200328200 on July 15, 2002

J. Biol. Chem., Vol. 277, Issue 36, 32405-32408, September 6, 2002
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ACCELERATED PUBLICATION
Inhibitory PAS Domain Protein (IPAS) Is a Hypoxia-inducible Splicing Variant of the Hypoxia-inducible Factor-3alpha Locus*

Yuichi MakinoDagger , Arvydas Kanopka§, William J. Wilson, Hirotoshi TanakaDagger ||, and Lorenz Poellinger||**

From the  Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden, the § Institute of Biotechnology, Graiciuno 8, 2028 Vilnius, Lithuania, and the Dagger  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 inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, functions as a dominant negative regulator of hypoxia-inducible transcription factors (HIFs) by forming complexes with those proteins that fail to bind to hypoxia response elements of target genes. We have previously observed that IPAS is predominantly expressed in mice in Purkinje cells of the cerebellum and in corneal epithelium of the eye where it appears to play a role in negative regulation of angiogenesis and maintenance of an avascular phenotype. Sequencing of the mouse IPAS genomic structure revealed that IPAS is a splicing variant of the HIF-3alpha locus. Thus, in addition to three unique exons (1a, 4a, and 16) IPAS shares three exons (2, 4, and 5) with HIF-3alpha as well as alternatively spliced variants of exons 3 and 6. In experiments using normal mice and mice exposed to hypoxia (6% O2) for 6 h we observed alternative splicing of the HIF-3alpha transcript in the heart and lung. The alternatively spliced transcript was only observed under hypoxic conditions, thus defining a novel mechanism of hypoxia-dependent regulation of gene expression. Importantly, this mechanism may establish negative feedback loop regulation of adaptive responses to hypoxia/ischemia in these tissues.

* This work was supported by the Swedish Medical Research Council, the Royal Swedish Academy of Science, The Swedish Heart and Lung Foundation, Japan Society for the Promotion of Science, Kanagawa Academy of Science and Technology, The Vehicle Racing Commemorative Foundation, the Cell Science Research Foundation, and the Ministry of Education, Culture, Sports, Science, and Technology of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF481145, AF481146, and AF481147.

|| Both authors should be considered equal last authors.

** To whom correspondence should be addressed: Dept. of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden. Tel.: 46-8-728-7330; Fax: 46-8-34-88-19; E-mail: lorenz.poellinger@cmb.ki.se.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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