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J. Biol. Chem., Vol. 279, Issue 34, 36048-36058, August 20, 2004

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Regulation of Drosophila Hypoxia-inducible Factor (HIF) Activity in SL2 Cells

IDENTIFICATION OF A HYPOXIA-INDUCED VARIANT ISOFORM OF THE HIF HOMOLOG GENE similar^*

Thomas A. Gorr, Takeshi Tomita, Pablo Wappner¶||, and H. Franklin Bunn**

From the Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and the ^¶Instituto Leloir, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Patricias Argentinas 435, Buenos Aires 1405, Argentina

Although hypoxia-inducible factor- (HIF) subunit-specific hydroxylation and proteolytic breakdown explain the binary switch between the presence (hypoxia) and absence (normoxia) of HIFs, little is known of the mechanisms that fine-tune HIF activity under constant, rather than changing, oxygen tensions. Here, we report that the Drosophila HIF homolog, the basic helix-loop-helix/PAS protein Sima (Similar), in hypoxic cultures of SL2 cells is expressed in full-length (fl) and splice variant (sv) isoforms. The following evidence supports the role of flSima as functional HIF and the role of SL2 HIF as a transcriptional activator or suppressor. The pO₂ dependence of Sima abundance matched that of HIF activity. HIF-dependent changes in candidate target gene expression were detected through variously effective stimuli: hypoxia (strong) > iron chelation, e.g. desferrioxamine (moderate) >> transition metals, e.g. cobalt normoxia (ineffective). Sima overexpression augmented hypoxic induction or suppression of different targets. In addition to the full-length exon 1–12 transcript yielding the 1510-amino acid HIF homolog, the sima gene also expressed, specifically under hypoxia, an exon 1–7/12 splice variant, which translated into a 426-amino acid Sima truncation termed svSima. svSima contains basic helix-loop-helix and PAS sequences identical to those of flSima, but, because of deletion of exons 8–11, lacks the oxygen-dependent degradation domain and nuclear localization signals. Overexpressed svSima failed to transactivate reporter genes. However, it attenuated HIF (Sima·Tango)-stimulated reporter expression in a dose-dependent manner. Thus, svSima has the potential to regulate Drosophila HIF function under steady and hypoxic pO₂ by creating a cytosolic sink for the Sima partner protein Tango.

Received for publication, May 7, 2004 , and in revised form, May 26, 2004.

^* This work was supported in part by National Institutes of Health Grant R01 DK41234. 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 Supplemental Fig. 1 and Supplemental Table 1.

Supported by the Uehara Memorial Foundation.

^|| Career Investigator of the Consejo Nacional de Investigaciones Científicas y Técnicas.

^** To whom correspondence should be addressed: Div. of Hematology, Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115. Tel.: 617-732-5841; Fax: 617-739-0748; E-mail: hfbunn{at}rics.bwh.harvard.edu.

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