title: Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression.
abstract: 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 1alpha (HIF-1alpha) 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-1alpha but not with ARNT1. The binding of HIF-1alpha 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.
authors.affiliation: Department of Pathology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan. fsato@cc.hirosaki-u.ac.jp
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Sato
authors.forename: Ujjal Kumar
authors.initials: UK
authors.lastname: Bhawal
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Katsumi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Tadanobu
authors.initials: T
authors.lastname: Imanaka
authors.forename: Jun
authors.initials: J
authors.lastname: Kondo
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Mitsuhide
authors.initials: M
authors.lastname: Noshiro
authors.forename: Hidemi
authors.initials: H
authors.lastname: Yoshida
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kusumi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012510:Sarcoma 180 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C497397:Arnt protein, mouse; C470968:Bhlhb3 protein, mouse; C491539:Bhlhe40 protein, mouse; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse