VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?

Biochem Biophys Res Commun. 2004 Aug 27;321(3):648-56. doi: 10.1016/j.bbrc.2004.06.176.

Abstract

The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcimycin / metabolism
  • Calcineurin / metabolism
  • Calcineurin Inhibitors
  • Cells, Cultured
  • Cyclooxygenase 2
  • DNA-Binding Proteins / metabolism
  • Down Syndrome
  • Endothelial Cells / cytology
  • Endothelial Cells / physiology*
  • Endothelium, Vascular / cytology
  • Enzyme Inhibitors / metabolism
  • Feedback, Physiological*
  • Gene Expression Regulation*
  • Genes, Reporter
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ionophores / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Membrane Proteins
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • NFATC Transcription Factors
  • Neovascularization, Physiologic*
  • Nuclear Proteins*
  • Promoter Regions, Genetic
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction / physiology
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor A / pharmacology

Substances

  • Calcineurin Inhibitors
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Ionophores
  • Isoenzymes
  • Membrane Proteins
  • Muscle Proteins
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Protein Isoforms
  • RCAN1 protein, human
  • RNA, Messenger
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Calcimycin
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Calcineurin