Down syndrome critical region 1 enhances the proteolytic cleavage of calcineurin

Exp Mol Med. 2009 Jul 31;41(7):471-7. doi: 10.3858/emm.2009.41.7.052.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adult
  • Animals
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Calcium-Binding Proteins
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins
  • Down Syndrome / metabolism*
  • Down Syndrome / pathology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Immunoglobulin G / immunology
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Muscle Proteins / physiology*
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Neurons / cytology
  • Neurons / metabolism
  • Oxidants / pharmacology
  • Oxidative Stress
  • Peptide Fragments / immunology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Rabbits
  • Reverse Transcriptase Polymerase Chain Reaction
  • Skin / pathology
  • Young Adult

Substances

  • Calcineurin Inhibitors
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • DSCR1 protein, mouse
  • Immunoglobulin G
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Oxidants
  • Peptide Fragments
  • RCAN1 protein, human
  • RNA, Messenger
  • RNA, Small Interfering
  • Hydrogen Peroxide
  • Calcineurin