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A Dominant-Negative Isoform of Hypoxia-Inducible Factor-1 Specifically Expressed in Human Testis¹

Institute of Physiology³ Clinic of Anaesthesiology,⁴ University of Lübeck, D-23538 Lübeck, Germany Cell Physiology Group,⁵ Medical Faculty, Martin-Luther-University Halle, D-06112 Halle, Germany Institute of Vegetative Physiology,⁶ D-50931 Cologne, Germany Institute of Physiology,⁷ University of Zürich, CH-8057 Zürich, Switzerland

Spermatogenesis in the seminiferous tubuli of the testis occurs under a high proliferation rate, suggesting considerable oxygen consumption. Because of the lack of blood vessels, the oxygen partial pressure in the lumen of these tubuli is very low. We previously identified a testis isoform of the hypoxia-inducible factor (HIF)-1 in the mouse, termed mHIF-1I.1. Here, we demonstrate that expression of mHIF-1I.1 increases during puberty, further demonstrating its gene induction in postmeiotic germ cells. Using 5'-rapid amplification of cDNA ends, we identified a novel HIF-1 isoform in the human testis, called hHIF-1Te. Like mHIF-1I.1, hHIF-1Te mRNA is derived from an alternative promoter-first exon combination, but with a different genomic organization and a different nucleotide sequence. Reverse transcription-polymerase chain reaction analysis confirmed that hHIF-1Te is exclusively expressed in the testis. As determined by immunofluorescence of ejaculated sperm cells, HIF-1 protein is mainly localized in the postacrosomal head and in the midpiece of spermatozoa. Though overlapping with mitochondrial localization in human and mouse spermatozoa, neither hHIF-1Te nor hHIF-1 associated with mitochondria. In contrast with the ubiquitously expressed HIF-1 protein and the mouse testis-specific mHIF-1I.1 isoform, the hHIF-1Te mRNA sequence predicts a protein with an N-terminal truncation of the DNA-binding domain. As shown by yeast two-hybrid assays, hHIF-1Te still formed heterodimeric complexes with HIF-1ß. However, hHIF-1Te was incapable of forming a DNA-binding HIF-1 complex. Overexpression of exogenous hHIF-1Te resulted in the inhibition of the endogenous HIF-1 transcriptional activity, demonstrating that the testis-specific hHIF-1Te isoform is a dominant-negative regulator of normal HIF-1 activity.

¹ Supported by the Deutsche Forschungsgemeinschaft (Ka1269/5-1), the German Ministry for Education and Research (NBL3) the Swiss National Science Foundation (31-104219/1), and the Research Program Reproduction Biology of the University of Lübeck. R.H.W. and D.M.K. contributed equally to this work.

² Correspondence: Roland H. Wenger, Institute of Physiology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. FAX: 41 0 1 63 56814; roland.wenger{at}access.unizh.ch

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