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The TCF‐4 signaling pathway negatively regulates HIF‐1a transcriptional activity in response to hypoxia
Author(s) -
Hao Wei,
Chou ChihLing,
Xu Wei,
Israel Davelene,
Hutchinson Anthony,
Ji Ruyue,
Regan John W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.829.6
Subject(s) - hypoxia (environmental) , reporter gene , angiogenesis , signal transduction , biology , hypoxia inducible factors , microbiology and biotechnology , gene , cancer research , chemistry , gene expression , genetics , oxygen , organic chemistry
Hypoxia inducible factor‐1α (HIF‐1α) plays an important role in cancer by helping cells survive under low oxygen conditions through the up‐regulation of genes that promote angiogenesis. Dysregulation of the β‐catenin/T‐cell factor (TCF) signaling pathway is also known to occur in several cancers; however, the relationship between up‐regulation of HIF‐1α and activation of TCF signaling has not been previously explored. The present study examines this relationship in a model system using RWPE‐1 prostate cells. HIF‐1α transcriptional activity was assessed using a luciferase reporter gene containing an upstream hypoxia response element (HRE). Cells were incubated under hypoxic conditions (1% O2, 5% CO2, 94% N2) for 24 hr and HRE reporter gene activity was assessed of either alone or following pre‐treatment with a dominant negative mutant of TCF‐4 (DN‐TCF‐4). In response to hypoxia, HRE reporter gene activity was increased relative to cells maintained under normoxic conditions. In cells pre‐treated with DN‐TCF‐4, HRE reporter gene activity was further increased in response to hypoxia as compared with cells exposed to hypoxia alone. These findings suggest that the TCF signaling pathway can negatively regulate the induction of HIF‐1α in cells exposed to hypoxia, which may be of significance to understanding the up‐regulation of HIF‐1 α that occurs in cancer. Supported by EY 11291.