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Is Constitutively Expressed in Murine Leydig Cells and Regulates 3β-Hydroxysteroid Dehydrogenase Type 1 Promoter Activity
From the Departments of * Urology and
Endocrinology, University of Virginia Health
System, Charlottesville, Virginia; The Centre
for Research in Biology of Reproduction, Department of Obstetrics and
Gynecology, Laval University, Quebec City, Canada; and the Departments of
Pediatrics and || Cell
Biology, University of Virginia Health System, Charlottesville,
Virginia.
| Correspondence to: Jeffrey J. Lysiak, Department of Urology, University of Virginia, Charlottesville, VA 22908 (e-mail: jl6n{at}virginia.edu). |
(HIF-1) is a transcription factor
that plays an essential role in oxygen homeostasis. HIF-1 is
constitutively made in cells; however, it is ubiquitinated and degraded under
normoxic conditions. Hypoxia prevents the ubiquitination of HIF-1,
resulting in stabilization of the protein and activation of target genes.
Because of its vascular arrangement and the high metabolic demand of
spermatogenesis, the testis has been described previously as functioning on
the brink of hypoxia; thus, we have hypothesized that HIF-1 is
constitutively expressed and stabilized in the testis, where it could play a
role in testicular homeostasis. Western blot analysis using nuclear proteins
from liver, kidney, and testis revealed the presence of HIF-1 only in
the testis. Immunohistochemistry confirmed this result and revealed that
HIF-1 was specifically located in interstitial Leydig cells.
Electromobility shift assays employing nuclear extracts from the TM3 Leydig
cell line revealed that these cells express HIF-1 that is capable of
binding DNA under normoxic conditions. Furthermore, we found that protein
levels can be increased further when the TM3 cells are cultured under hypoxic
conditions. Finally, transient transfections of TM3 Leydig cells revealed that
the promoter of the mouse 3β-hydroxysteroid dehydrogenase type 1 (Hsd3b1)
gene, which encodes a key enzyme in testosterone production, is a potential
target of HIF-1. In conclusion, HIF-1 is constitutively present
in the Leydig cells of the murine testis, where it potentially regulates
Hsd3b1 transcription, and thus male reproductive function.
Key words: Reproductive tract, steroidogenesis, testis
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