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Genes to Cells (2008) 13, 131-144. doi:10.1111/j.1365-2443.2007.01153.x
© 2008 Blackwell Publishing or its licensors
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Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression

 Fuyuki Sato1,*, Ujjal Kumar Bhawal2, Takeshi Kawamoto3, Katsumi Fujimoto3, Tadaatsu Imaizumi4, Tadanobu Imanaka5, Jun Kondo1, Satoru Koyanagi6, Mitsuhide Noshiro3, Hidemi Yoshida4, Tomomi Kusumi1, Yukio Kato3 and Hiroshi Kijima1

1 Department of Pathology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
2 Department of Oral Maxillofacial Diagnostic Science, Division of Pathology and High-Tech Research Center, Kanagawa Dental College, Kanagawa, 238-8580, Japan
3 Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan
4 Department of Vascular Biology, Institute of Brain Science, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan
5 Department of the Biology and Medicine of the Stem Cell, Hiroshima University Graduate School of Medical Science, Hiroshima 734-8553, Japan
6 Department of Medico-Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

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 1{alpha} (HIF-1{alpha}) 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-1{alpha} but not with ARNT1. The binding of HIF-1{alpha} 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.

Communicated by: Masayuki Yamamoto (Tohoku University)

* Correspondence: E-mail: fsato{at}cc.hirosaki-u.ac.jp






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