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

Gangjian Qin; Raj Kishore; Christine M. Dolan; Marcy Silver; Andrea Wecker; Corinne N. Luedemann; Tina Thorne; Allison Hanley; Cynthia Curry; Lindsay Heyd; Deepika Dinesh; Marianne Kearney; Fabio Martelli; Toshinori Murayama; David A. Goukassian; Yan Zhu; Douglas W. Losordo

doi:10.1073/pnas.0509533103

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

Gangjian Qin^*, Raj Kishore, Christine M. Dolan, Marcy Silver, Andrea Wecker, Corinne N. Luedemann, Tina Thorne, Allison Hanley, Cynthia Curry, Lindsay Heyd, Deepika Dinesh, Marianne Kearney, Fabio Martelli, Toshinori Murayama, David A. Goukassian, Yan Zhu, Douglas W. Losordo

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

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 endothetial 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.

Original language	English (US)
Pages (from-to)	11015-11020
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	29
DOIs	https://doi.org/10.1073/pnas.0509533103
State	Published - Jul 18 2006

Keywords

E2F
Endothelial cell

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Qin, G., Kishore, R., Dolan, C. M., Silver, M., Wecker, A., Luedemann, C. N., Thorne, T., Hanley, A., Curry, C., Heyd, L., Dinesh, D., Kearney, M., Martelli, F., Murayama, T., Goukassian, D. A., Zhu, Y., & Losordo, D. W. (2006). 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, 103(29), 11015-11020. https://doi.org/10.1073/pnas.0509533103

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title = "Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF",

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 endothetial 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.",

keywords = "E2F, Endothelial cell",

author = "Gangjian Qin and Raj Kishore and Dolan, {Christine M.} and Marcy Silver and Andrea Wecker and Luedemann, {Corinne N.} and Tina Thorne and Allison Hanley and Cynthia Curry and Lindsay Heyd and Deepika Dinesh and Marianne Kearney and Fabio Martelli and Toshinori Murayama and Goukassian, {David A.} and Yan Zhu and Losordo, {Douglas W.}",

year = "2006",

month = jul,

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doi = "10.1073/pnas.0509533103",

language = "English (US)",

volume = "103",

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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 2006, '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, pp. 11015-11020. https://doi.org/10.1073/pnas.0509533103

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T1 - Cell cycle regulator E2F1 modulates angiogenesis via p53-dependent transcriptional control of VEGF

AU - Qin, Gangjian

AU - Kishore, Raj

AU - Dolan, Christine M.

AU - Silver, Marcy

AU - Wecker, Andrea

AU - Luedemann, Corinne N.

AU - Thorne, Tina

AU - Hanley, Allison

AU - Curry, Cynthia

AU - Heyd, Lindsay

AU - Dinesh, Deepika

AU - Kearney, Marianne

AU - Martelli, Fabio

AU - Murayama, Toshinori

AU - Goukassian, David A.

AU - Zhu, Yan

AU - Losordo, Douglas W.

PY - 2006/7/18

Y1 - 2006/7/18

N2 - 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 endothetial 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.

AB - 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 endothetial 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.

KW - E2F

KW - Endothelial cell

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JF - Proceedings of the National Academy of Sciences of the United States of America

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ER -

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

Abstract

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