Abstract
Down syndrome critical region 1 (DSCR1), an oxidative stress-response gene, interacts with calcineurin and represses its phosphatase activity. Recently it was shown that hydrogen peroxide inactivates calcineurin by proteolytic cleavage. Based on these facts, we investigated whether oxidative stress affects DSCR1- mediated inactivation of calcineurin. We determined that overexpression of DSCR1 leads to increased proteolytic cleavage of calcineurin. Convertsely, knockdown of DSCR1 abolished calcineurin cleavage upon treatment with hydrogen peroxide. The PXIIXT motif in the COOH-terminus of DSCR1 is responsible for both binding and cleavage of calcineurin. The knockdown of overexpressed DSCR1 in DS fibroblast cells also abrogated calcineurin proteolysis by hydrogen peroxide. These results suggest that DSCR1 has the ability to inactivate calcineurin by inducing proteolytic cleavage of calcineurin upon oxidative stress.
Highlights
Calcineurin, a calcium and calmodulin-dependent protein serine/ threonine phosphatase plays a critical role in various biological processes
When we transfected SK-N-SH cells with mammalian expression vectors for calcineurin and its endogenous inhibitors, we found that Down syndrome critical region 1 (DSCR1) overexpression resulted in proteolytic cleavage of calcineurin, similar to H2O2 (Figure 1A)
DSCR1 interacts with the CNA catalytic subunit and inhibits calcineurin phosphatase activity (Rothermel et al, 2000; Vega et al, 2002; Chan et al, 2005; Aubareda et al, 2006)
Summary
Calcineurin ( known as protein phosphatase 3), a calcium and calmodulin-dependent protein serine/ threonine phosphatase plays a critical role in various biological processes. Calcineurin is involved in the regulation of T cell development, heart valve and myocardial development, and in neuronal memory and learning (Aramburu et al, 2000; Crabtree 2001). Down syndrome critical region 1 (DSCR1) belongs to a family of evolutionarily conserved proteins that can directly bind and inhibit calcineurin (Fuentes et al, 2000; Kingsbury and Cunningham, 2000; Ermak et al, 2002). DSCR1 is involved in the regulation of various cellular functions (Harris et al, 2005). It is overexpressed in the brains of Down Syndrome (DS) fetuses and in post-mortem brain samples from AD patients (Fuentes et al, 2000; Ermak et al, 2001). DSCR1, induced by VEGF, TNF-α, and calcium ionophore, participates in endothelial cell migration and angiogenesis (Iizuka et al, 2004; Yao and Duh, 2004)
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