XIAP regulates intracellular ROS by enhancing antioxidant gene expression

Biochem Biophys Res Commun. 2008 Oct 10;375(1):156-61. doi: 10.1016/j.bbrc.2008.07.142. Epub 2008 Aug 8.

Abstract

XIAP (X chromosome-linked inhibitor of apoptosis) is a member of the anti-apoptotic IAP gene family and an inhibitor of caspase-3. We show here that loss of XIAP renders cells highly sensitive to oxidative stress. Stimulation of XIAP(-/-) MEF with hydrogen peroxide, or other agents that generate reactive oxygen species (ROS) results in increased apoptosis assessed by caspase-3 activity and PARP cleavage. Furthermore, we observed increased levels of ROS and diminished expression of antioxidative genes, e.g., SOD1, -2, NQO1, HO-1, and Txn2 in XIAP(-/-) cells. In addition, stimulation of XIAP(-/-) MEF with hydrogen peroxide resulted in enhanced phosphorylation of JNK. Our findings reveal that XIAP, in addition to its well described caspase-inhibitory function, prevents prolonged JNK activation and is critically involved in modulating ROS levels through regulation of antioxidative genes, thereby inhibiting ROS-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Apoptosis* / genetics
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Gene Expression / drug effects
  • Gene Expression Regulation*
  • Hydrogen Peroxide / pharmacology
  • MAP Kinase Kinase 4 / metabolism
  • Mice
  • Mice, Mutant Strains
  • Oxidoreductases / genetics*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Reactive Oxygen Species / metabolism*
  • X-Linked Inhibitor of Apoptosis Protein / genetics
  • X-Linked Inhibitor of Apoptosis Protein / physiology*

Substances

  • Antioxidants
  • Reactive Oxygen Species
  • X-Linked Inhibitor of Apoptosis Protein
  • Hydrogen Peroxide
  • Oxidoreductases
  • Poly(ADP-ribose) Polymerases
  • MAP Kinase Kinase 4
  • Caspase 3