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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcimycin / metabolism
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Calcineurin / metabolism
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Calcineurin Inhibitors
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Cells, Cultured
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Cyclooxygenase 2
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DNA-Binding Proteins / metabolism
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Down Syndrome
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Endothelial Cells / cytology
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Endothelial Cells / physiology*
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Endothelium, Vascular / cytology
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Enzyme Inhibitors / metabolism
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Feedback, Physiological*
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Gene Expression Regulation*
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Genes, Reporter
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Humans
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Intracellular Signaling Peptides and Proteins
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Ionophores / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Membrane Proteins
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Muscle Proteins / genetics*
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Muscle Proteins / metabolism
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NFATC Transcription Factors
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Neovascularization, Physiologic*
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Nuclear Proteins*
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Promoter Regions, Genetic
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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RNA, Messenger / metabolism
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Signal Transduction / physiology
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Transcription Factors / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor A / pharmacology
Substances
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Calcineurin Inhibitors
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DNA-Binding Proteins
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Ionophores
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Isoenzymes
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Membrane Proteins
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Muscle Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Protein Isoforms
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RCAN1 protein, human
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RNA, Messenger
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Calcimycin
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Calcineurin