Basic-helix-loop-helix (bHLH) transcription factor DEC2 negatively regulates vascular endothelial growth factor expression.
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.
Sato
Fuyuki
F
Department of Pathology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan. fsato@cc.hirosaki-u.ac.jp
Bhawal
Ujjal Kumar
UK
Kawamoto
Takeshi
T
Fujimoto
Katsumi
K
Imaizumi
Tadaatsu
T
Imanaka
Tadanobu
T
Kondo
Jun
J
Koyanagi
Satoru
S
Noshiro
Mitsuhide
M
Yoshida
Hidemi
H
Kusumi
Tomomi
T
Kato
Yukio
Y
Kijima
Hiroshi
H
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*
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