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Two splice variants of the hypoxia‐inducible factor HIF‐1α as potential dimerization partners of ARNT2 in neurons
Author(s) -
Drutel Guillaume,
Kathmann Markus,
Héron Anne,
Gros Claude,
Macé Séverine,
Schwartz JeanCharles,
Arrang JeanMichel
Publication year - 2000
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2000.00266.x
Subject(s) - aryl hydrocarbon receptor nuclear translocator , transcription factor , downregulation and upregulation , biology , microbiology and biotechnology , hypoxia inducible factor 1 , gene , transcription (linguistics) , biochemistry , aryl hydrocarbon receptor , linguistics , philosophy
The hypoxia‐inducible factor (HIF‐1α), a basic helix‐loop‐helix transcription factor, is known to heterodimerize with ARNT1, a nuclear translocator, to trigger the overexpression in many cells of genes involved in resistance to hypoxia. Although HIF‐1α and ARNT1 are both expressed in brain, their cellular localization and function therein are unknown. Here, using in situ hybridization and immunocytochemistry, we show that HIF‐1α is expressed in normoxic cerebral neurons together with not only ARNT1 but also ARNT2, a cerebral translocator homologous to ARNT1 but displaying, unlike ARNT1, a selective neuronal expression. In contrast, other potential partners of the translocators, i.e. the aryl hydrocarbon receptor (AHR) and the single‐minded protein 2 (SIM2), are not expressed in the adult brain. We also identify two splice variants of HIF‐1α in brain, one of which dimerizes with ARNT2 even more avidly than with ARNT1. The resulting heterodimer, in contrast with the HIF‐1α/ARNT1 complex, does not recognize the HIF‐1‐binding site of the hypoxia‐induced erythropoietin (Epo) gene, suggesting that it controls transcription of a distinct set of genes. We therefore propose that HIF‐1α and ARNT2 function as preferential dimerization partners in neurons to control specific responses, some of which may not be triggered by hypoxia. In support of this proposal, in nonhypoxic PC12 cells constitutively coexpressing HIF‐1α, ARNT1 and ARNT2, downregulation of either HIF‐1α or ARNT2, obtained with selective antisense nucleotides, resulted in inhibition of [ 3 H]thymidine incorporation.