Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF.
The transcription factor E2F1 is known to regulate cell proliferation and has been thought to modulate tumorigenesis via this mechanism alone. Here we show that mice deficient in E2F1 exhibit enhanced angiogenesis. The proangiogenic phenotype in E2F1 deficiency is the result of overproduction of vascular endothelial growth factor (VEGF) and is prevented by VEGF blockade. Under hypoxic conditions, E2F1 down-regulates the expression of VEGF promoter activity by associating with p53 and specifically down-regulating expression of VEGF but not other hypoxia-inducible genes, suggesting a promoter structure context-dependent regulation mechanism. We found that the minimum VEGF promoter mediating transcriptional repression by E2F1 features an E2F1- binding site with four Sp-1 sites in close proximity. These data disclose an unexpected function of endogenous E2F1: regulation of angiogenic activity via p53-dependent transcriptional control of VEGF expression.
Qin
Gangjian
G
Division of Cardiovascular Research, Tufts University School of Medicine, Caritas St. Elizabeth's Medical Center, Boston, MA 02135, USA. gangjian.qin@tuffs.edu
Kishore
Raj
R
Dolan
Christine M
CM
Silver
Marcy
M
Wecker
Andrea
A
Luedemann
Corinne N
CN
Thorne
Tina
T
Hanley
Allison
A
Curry
Cynthia
C
Heyd
Lindsay
L
Dinesh
Deepika
D
Kearney
Marianne
M
Martelli
Fabio
F
Murayama
Toshinori
T
Goukassian
David A
DA
Zhu
Yan
Y
Losordo
Douglas W
DW
D000818:Animals; D002453:Cell Cycle; D002478:Cells, Cultured; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014158:Transcription, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics*
D050687:E2F1 Transcription Factor; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A