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

Research output: Contribution to journalArticle

18 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 languageEnglish (US)
Pages (from-to)255-261
Number of pages7
JournalMolecular and Cellular Biochemistry
Volume338
Issue number1-2
DOIs
StatePublished - May 1 2010

Keywords

  • Endothelial cell
  • HIF
  • HUVEC
  • Hypoxia
  • Serpinf1

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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    Lee, S., Nguyen, T. M. B., Kovalenko, D., Adhikari, N., Grindle, S., Polster, S. P., Friesel, R., Ramakrishnan, S., & Hall, J. L. (2010). Sprouty1 inhibits angiogenesis in association with up-regulation of p21 and p27. Molecular and Cellular Biochemistry, 338(1-2), 255-261. https://doi.org/10.1007/s11010-009-0359-z