＜Symposium I＞Vascular endothelial growth factor（ VEGF） expression is negatively regulated by basic-helix-loop-helix（ bHLH）transcription factor DEC2

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The circadian rhythms in mammals are regulated by a pacemaker located in the suprachiasmatic nucleusof the hypothalamus. Five clock-gene families, i.e. Clock, Bmal, Per, Cry and Dec, have been found to be involved ina transcription-translation feedback loop that generates the circadian rhythm at the intracellular level. In this study,we examined functional analysis of the Dec gene. DEC1 and DEC2 are basic-helix-loop-helix （bHLH） transcriptionfactors, involved in cellular diff erentiation, responses to hypoxia, and circadian rhythms. We recently showed thatthe expression of DEC1 and DEC2 was upregulated by hypoxia, however, the functions of these two factors underhypoxic conditions have not been elucidated in detail. It is well established that the expression of vascular endothelialgrowth factor （VEGF） is upregulated by hypoxia, and the expression of VEGF in response to hypoxia depends ontranscriptional activation by a heterodimer comprising hypoxia-inducible factor 1 α （HIF-1α） and arylhydrocarbonreceptor nuclear translocator 1 （ARNT1）. In the present study, we showed that DEC2, but not DEC1, suppressedVEGF gene expression under hypoxic conditions. DEC2 protein was co-immunoprecipitated with HIF-1α but notwith ARNT1. The binding of HIF-1α to the hypoxia response element（ HRE） in the VEGF promoter was decreasedby DEC2 overexpression, and increased by DEC2 knockdown. We also showed that the circadian expression ofVEGF showed a reciprocal pattern to that of DEC2 in cartilage. DEC2 had a circadian oscillation in implantedSarcoma 180 cells. We conclude that DEC2 negatively regulates VEGF expression and plays an important role in thepathological conditions in which VEGF is involved.

＜Symposium I＞Vascular endothelial growth factor（ VEGF） expression is negatively regulated by basic-helix-loop-helix（ bHLH）transcription factor DEC2

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