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Originally published In Press as doi:10.1074/jbc.M104782200 on October 15, 2001

J. Biol. Chem., Vol. 276, Issue 52, 48754-48763, December 28, 2001
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Differential Regulation of Two Alternatively Spliced Isoforms of Hypoxia-inducible Factor-1alpha in Activated T Lymphocytes*

Dmitriy Lukashev, Charles Caldwell, Akio Ohta, Pearl Chen, and Michail SitkovskyDagger

From the Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892

Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent up-regulation of HIF-1alpha subunit in antigen receptor-activated T cells. This is explained by a selective up-regulation of alternatively spliced mRNA isoform I.1 that encodes the HIF-1alpha protein without the first 12 N-terminal amino acids. We show that both short (I.1) and long (I.2) HIF-1alpha isoforms display similar DNA binding and transcriptional activities. Major differences were observed between these two HIF-1alpha isoforms in their expression patterns with respect to the resting and activated T lymphocytes in hypoxic and normoxic conditions. The T cell antigen receptor (TCR)-triggered activation of normal ex vivo T cells and differentiated T cells results in up-regulation of expression of I.1 isoform of HIF-1alpha mRNA without an effect on constitutive I.2 HIF-1alpha mRNA expression. The accumulation of I.1 HIF-1alpha mRNA isoform in T lymphocytes is also demonstrated during cytokine-mediated inflammation in vivo, suggesting a physiological role of short HIF-1alpha isoform in activated lymphocytes. The TCR-triggered, protein kinase C and Ca2+/calcineurin-mediated HIF-1alpha I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1alpha I.1 gene is expressed as an immediate early response gene. Therefore, these data predict a different physiological role of short and long isoforms of HIF-1alpha in resting and activated cells.

* 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.

Dagger To whom correspondence should be addressed: Bldg. 10, Rm. 11N311, Laboratory of Immunology, NIAID, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-5495; Fax: 301-480-7352; E-mail: mvsitkov@helix.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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