Hypoxia-inducible factor 1 mediates upregulation of telomerase (hTERT).
Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1alpha (HIF-1alpha) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between -165 and +51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.
Nishi
Hirotaka
H
Department of Obstetrics and Gynecology, Tokyo Medical University, Japan. nishih@tokyo-med.ac.jp
Nakada
Toshihide
T
Kyo
Satoru
S
Inoue
Masaki
M
Shay
Jerry W
JW
Isaka
Keiichi
K
D002455:Cell Division; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005865:Gestational Age; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000502:physiology*; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors; D015533:Transcriptional Activation; D014327:Trophoblasts / Q000166:cytology; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D019098:Telomerase