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J Biol Chem, Vol. 275, Issue 10, 6922-6927, March 10, 2000

Identification of Alternative Spliced Variants of Human Hypoxia-inducible Factor-1alpha *

Emmanuel GothiéDagger , Darren E. Richard§, Edurne Berra, Gilles Pagès, and Jacques Pouysségur

From the Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre Antoine Lacassagne, 33 Avenue Valombrose, 06189 Nice, France

Mammalian cells are able to sense oxygen and regulate a number of genes in response to hypoxia. The transcription factor Hypoxia Inducible Factor-1 (HIF-1) was identified as an important key component of the hypoxia signaling pathway. HIF-1 is a heterodimer composed of two members of the basic helix-loop-helix transcription factor superfamily containing a PAS (PER-ARNT-SIM) domain: HIF-1alpha and HIF-1beta /ARNT. During the cloning by reverse transcriptase-polymerase chain reaction of the human HIF-1alpha subunit, we isolated two cDNA clones which corresponded to alternative splicing of the HIF-1alpha gene. Polymerase chain reaction analysis and sequencing revealed that both clones possessed three additional base pairs between exons 1 and 2. Also, one of them lacked 127 base pairs corresponding to exon 14. We demonstrate that the mRNA of this truncated form is expressed in several human cells lines and human skin but apparently not in rodents. When transfected in HEK 293 cells, the corresponding 736 amino acid protein (HIF-1alpha 736) is regulated by hypoxia in a similar manner as the full-length HIF-1alpha (HIF-1alpha FL). In luciferase transfection assays, both recombinant proteins HIF-1alpha 736 and HIF-1alpha FL dimerize with HIF-1beta /ARNT and activate the VEGF promoter upon hypoxia. However, the shorter HIF-1alpha isoform is 3-fold less active than HIF-1alpha FL, a result consistent with the lack of the C-terminal transactivation domain. As expected, this small isoform can compete with the endogenous and transfected full-length HIF-1alpha . Altogether, these results suggest that the HIF-1alpha 736 isoform modulates gene expression upon hypoxia.

* This work was supported by grants from the Centre National de la Recherche Scientifique (CNRS), Le Ministère de la Recherche (ACC-SV9), La Ligue Nationale Contre le Cancer, l'Association pour la Recherche contre le Cancer (ARC), and the European Community (contract B104-CT97-2071).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 Recipient of a scholarship from CNRS and Roussel Uclaf and to whom correspondence should be addressed. Tel.: 33-4 92 03 12 38; Fax: 33-4 92 03 12 25; E-mail: gothie@unice.fr.

§ Supported by a fellowship from ELF-Aquitaine.

Recipient of a fellowship from the Human Frontier Science Program.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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