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Basic‐helix‐loop‐helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression
Author(s) -
Sato Fuyuki,
Bhawal Ujjal Kumar,
Kawamoto Takeshi,
Fujimoto Katsumi,
Imaizumi Tadaatsu,
Imanaka Tadanobu,
Kondo Jun,
Koyanagi Satoru,
Noshiro Mitsuhide,
Yoshida Hidemi,
Kusumi Tomomi,
Kato Yukio,
Kijima Hiroshi
Publication year - 2008
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01153.x
Subject(s) - biology , basic helix loop helix , transcription factor , vascular endothelial growth factor , medicine , endocrinology , microbiology and biotechnology , cancer research , dna binding protein , vegf receptors , gene , biochemistry
DEC1 (BHLHB2/Sharp2/Stra13) and DEC2 (BHLHB3/Sharp1) are basic‐helix‐loop‐helix (bHLH) transcription factors, involved in cellular differentiation, responses to hypoxia and circadian rhythms. We recently showed that the expression of DEC1 and DEC2 was up‐regulated by hypoxia; however, the functions of these two factors under hypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelial growth factor (VEGF) is up‐regulated by hypoxia, and the expression of VEGF in response to hypoxia depends on transcriptional activation by a heterodimer comprising hypoxia‐inducible factor 1α (HIF‐1α) and arylhydrocarbon receptor nuclear translocator 1 (ARNT1). In the present study, we showed that DEC2, but not DEC1, suppressed VEGF gene expression under hypoxic conditions. DEC2 protein was co‐immunoprecipitated with HIF‐1α but not with ARNT1. The binding of HIF‐1α to the hypoxia response element (HRE) in the VEGF promoter was decreased by DEC2 over‐expression, and increased by DEC2 knockdown. We also showed that the circadian expression of VEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implanted Sarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in the pathological conditions in which VEGF is involved.