Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2008-02, Vol.13 (2), p.131-144
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Binding Sites - genetics; Cell Hypoxia - genetics; Cell Line, Tumor; Cercopithecus aethiops; COS Cells; Gene Expression Regulation; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice; Mice, Inbred C57BL; NIH 3T3 Cells; Plasmids - genetics; Promoter Regions, Genetic; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Small Interfering - genetics; Sarcoma 180 - genetics; Sarcoma 180 - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Vascular Endothelial Growth Factor A - genetics
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1365-2443.2007.01153.x

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.