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J. Biol. Chem., Vol. 282, Issue 17, 12707-12716, April 27, 2007

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Mammalian Tumor Suppressor Int6 Specifically Targets Hypoxia Inducible Factor 2 for Degradation by Hypoxia- and pVHL-independent Regulation^*

Li Chen, Kazuyo Uchida, Alexander Endler, and Futoshi Shibasaki¹

From the Translation Research Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan and the Department of Biology, School of Basic Medicine, Tongji University, 1239 Siping Road, Shanghai 2000092, China

The hypoxia-inducible factors HIF-1 and HIF-2 are structurally similar as regards their DNA-binding and dimerization domains, but differ in their transactivation domains and, as is shown by experiments using hif-1^-/- and hif-2^-/- mice, in their functions. This implies that HIF-1 and HIF-2 may have unique target genes. To address this discrepancy and identify HIF-2-specific target genes, we performed yeast two-hybrid analysis and identified the tumor suppressor Int6/eIF3e/p48 as a novel target gene product involved in HIF-2 regulation. The int6 gene was first identified from a screen in which the mouse mammary tumor virus was employed as an insertional mutagen to identify genes whose functions are critical for breast tumor formation. Here, by using two-hybrid analysis, immunoprecipitation in mammalian cells, and HRE-reporter assays, we report the specific interaction of HIF-2 (but not HIF-1 or HIF-3) with Int6. The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2 degradation. This degradation was clearly observed in renal cell carcinoma 786-O cells, and was found to be both hypoxia- and pVHL-independent. Furthermore, Int6 protein knockdown by int6-siRNA vectors or the dominant-negative mutant Int6-C increased endogenous HIF-2 expression, even under normoxia, and induced sets of critical angiogenic factors comprising vascular endoplasmic growth factor, angiopoietin, and basic fibroblast growth factor mRNA. These results indicate that Int6 is a novel and critical determinant of HIF-2-dependent angiogenesis as well as cancer formation, and that int6-siRNA transfer may be an effective therapeutic strategy in pathological conditions such as heart and brain ischemia, hepatic cirrhosis, and obstructive vessel diseases.

Received for publication, January 16, 2007 , and in revised form, February 22, 2007.

^* This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to F. S.) and the Human Science Foundation (to F. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed. Tel.: 81-3-3823-0090; Fax: 81-3-3823-0085; E-mail: fshibasa{at}rinshoken.or.jp.

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