Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27

Sangjin Lee; Tri M.Bui Nguyen; Dmitry Kovalenko; Neeta Adhikari; Suzanne Grindle; Sean P. Polster; Robert Friesel; Sundaram Ramakrishnan; Jennifer L. Hall

doi:10.1007/s11010-009-0359-z

Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27

Sangjin Lee, Tri M.Bui Nguyen, Dmitry Kovalenko, Neeta Adhikari, Suzanne Grindle, Sean P. Polster, Robert Friesel, Sundaram Ramakrishnan, Jennifer L. Hall

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28 Scopus citations

Abstract

Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.

Original language	English (US)
Pages (from-to)	255-261
Number of pages	7
Journal	Molecular and cellular biochemistry
Volume	338
Issue number	1-2
DOIs	https://doi.org/10.1007/s11010-009-0359-z
State	Published - May 2010

Bibliographical note

Funding Information:
Acknowledgments This work was supported by a grant-in-aid from the American Heart Association (JH, 06555827) and NIH grants RO1 HL65301 and P20 RR15555 to RF. We thank Dr. Vercellotti’s lab at the University of Minnesota for providing HUVECs, Dr. Clohisy’s lab at the University of Minnesota for help with resources and Jenny Springsteen and the facilities staff under her direction in the Lillehei Heart Institute, and Ken Stern for his help in the preparation of this manuscript. Finally, we thank Dr. Lorrie Kirshenbaum at the University of Manitoba for his helpful discussions with this project.

Keywords

Endothelial cell
HIF
HUVEC
Hypoxia
Serpinf1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s11010-009-0359-z

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title = "Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27",

abstract = "Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.",

keywords = "Endothelial cell, HIF, HUVEC, Hypoxia, Serpinf1",

author = "Sangjin Lee and Nguyen, {Tri M.Bui} and Dmitry Kovalenko and Neeta Adhikari and Suzanne Grindle and Polster, {Sean P.} and Robert Friesel and Sundaram Ramakrishnan and Hall, {Jennifer L.}",

note = "Funding Information: Acknowledgments This work was supported by a grant-in-aid from the American Heart Association (JH, 06555827) and NIH grants RO1 HL65301 and P20 RR15555 to RF. We thank Dr. Vercellotti{\textquoteright}s lab at the University of Minnesota for providing HUVECs, Dr. Clohisy{\textquoteright}s lab at the University of Minnesota for help with resources and Jenny Springsteen and the facilities staff under her direction in the Lillehei Heart Institute, and Ken Stern for his help in the preparation of this manuscript. Finally, we thank Dr. Lorrie Kirshenbaum at the University of Manitoba for his helpful discussions with this project.",

year = "2010",

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doi = "10.1007/s11010-009-0359-z",

language = "English (US)",

volume = "338",

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AU - Nguyen, Tri M.Bui

AU - Kovalenko, Dmitry

AU - Adhikari, Neeta

AU - Grindle, Suzanne

AU - Polster, Sean P.

AU - Friesel, Robert

AU - Ramakrishnan, Sundaram

AU - Hall, Jennifer L.

N1 - Funding Information: Acknowledgments This work was supported by a grant-in-aid from the American Heart Association (JH, 06555827) and NIH grants RO1 HL65301 and P20 RR15555 to RF. We thank Dr. Vercellotti’s lab at the University of Minnesota for providing HUVECs, Dr. Clohisy’s lab at the University of Minnesota for help with resources and Jenny Springsteen and the facilities staff under her direction in the Lillehei Heart Institute, and Ken Stern for his help in the preparation of this manuscript. Finally, we thank Dr. Lorrie Kirshenbaum at the University of Manitoba for his helpful discussions with this project.

PY - 2010/5

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N2 - Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.

AB - Sprouty1 (Spry1) is a conserved antagonist of FGF signaling. The goal of this study was to further explore the downstream mechanisms governing Spry1 inhibition of endothelial cell proliferation. Up-regulation of Spry1 in HUVECs inhibited tube formation on Matrigel (n = 6, P < 0.001). This was associated with decreased proliferation as measured by BrdU incorporation (n = 6, P < 0.001) and increased protein expression of the cyclin-dependent kinase inhibitor 1A (CDKN1A), p21 and cyclin-dependent kinase inhibitor 1B (CDKN1B), p27. A transcriptional analysis using a targeted human angiogenesis array following up-regulation of Spry1 demonstrated a >2-fold increase in an anti-angiogenic factor, serpin peptidase inhibitor, clad F (Serpinf1), and a >2-fold decrease in pro-angiogenic factors fms-related tyrosine kinase 1 (FLT1), angiopoietin2 (Ang-2), and placental growth factor (PGF) (n = 2). To define upstream mechanisms that may regulate endogenous Spry1, we performed a search for responsive elements upstream of the promoter region. This search resulted in the identification of multiple degenerate hypoxia responsive elements. Exposure to hypoxia resulted in a significant increase in Spry1 expression (n = 8, P < 0.01). These findings shed new light on downstream signaling pathways associated with Spry1 anti-proliferative responses, and provide new evidence that hypoxia stimulates Spry1 expression.

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Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27

Abstract

Bibliographical note

Keywords

UN SDGs

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