XIAP regulates intracellular ROS by enhancing antioxidant gene expression.
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.
Resch
Ulrike
U
Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Lazarettg. 19, A-1090 Vienna, Austria. Ulrike.resch@meduniwien.ac.at
Schichl
Yvonne M
YM
Sattler
Susanne
S
de Martin
Rainer
R
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010088:Oxidoreductases / Q000235:genetics*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000502:physiology*
D000975:Antioxidants; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D011065:Poly(ADP-ribose) Polymerases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3