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PMID: 16835303 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 29 ·2006-07-18 ·Pages 11015-20

Qin G, Kishore R, Dolan CM, Silver M, Wecker A, Luedemann CN, Thorne T, Hanley A, Curry C, Heyd L, Dinesh D, Kearney M, Martelli F, Murayama T, Goukassian DA, Zhu Y, Losordo DW

Abstract

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.

MeSH Terms
Animals Cell Cycle Cells, Cultured Down-Regulation E2F1 Transcription Factor/deficiency,genetics,metabolism Hindlimb/blood supply,metabolism Humans Mice Mice, Inbred C57BL Mice, Knockout Transcription, Genetic/genetics Tumor Suppressor Protein p53/genetics,metabolism Vascular Endothelial Growth Factor A/biosynthesis,genetics
Chemicals
E2F1 Transcription Factor Tumor Suppressor Protein p53 Vascular Endothelial Growth Factor A
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Qin Gangjian
Division of Cardiovascular Research, Tufts University School of Medicine, Caritas St. Elizabeth's Medical Center, Boston, MA 02135, USA. [email protected]
Kishore Raj
Dolan Christine M
Silver Marcy
Wecker Andrea
Luedemann Corinne N
Thorne Tina
Hanley Allison
Curry Cynthia
Heyd Lindsay
Dinesh Deepika
Kearney Marianne
Martelli Fabio
Murayama Toshinori
Goukassian David A
Zhu Yan
Losordo Douglas W
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0509533103
Email
[email protected]
Published
2006-07-18
Epub
2006-00-11
Pages
11015-20
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1544166
Subset
IM
Grants
NHLBI NIH HHS · R01 HL077428 · United States
NHLBI NIH HHS · R01 HL080137 · United States
NHLBI NIH HHS · R01 HL057516 · United States
NHLBI NIH HHS · HL-57516 · United States
NHLBI NIH HHS · HL-53354 · United States
NHLBI NIH HHS · P01 HL066957 · United States
NHLBI NIH HHS · R01 HL063414 · United States
NHLBI NIH HHS · HL-80137 · United States
NHLBI NIH HHS · HL-77428 · United States
NHLBI NIH HHS · HL-66957 · United States
NHLBI NIH HHS · R37 HL053354 · United States
NHLBI NIH HHS · HL-63414 · United States
NHLBI NIH HHS · R01 HL053354 · United States
External Links
PubMed source DOI: 10.1073/pnas.0509533103 PMC Full Text View journal details
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