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

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

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