title: XIAP associates with GSK3 and inhibits the promotion of intrinsic apoptotic signaling by GSK3.
abstract: This study examined if there are interactions between two key proteins that oppositely regulate intrinsic apoptosis, X-linked inhibitor of apoptosis protein (XIAP), a key suppressor of apoptosis that binds to inhibit active caspases, and glycogen synthase kinase-3 (GSK3), which promotes intrinsic apoptosis. Immunoprecipitation of GSK3beta revealed that XIAP associates with GSK3beta, as do two other members of the IAP family, cIAP-1, and cIAP-2. Cell fractionation revealed that XIAP is predominantly cytosolic, cIAP-1 is predominantly nuclear and nearly all of the nuclear cIAP-1 and cIAP-2 are associated with GSK3. Expression of individual domains of XIAP demonstrated that the RING domain of XIAP associates with GSK3. Inhibition of GSK3 did not alter the binding of XIAP to active caspase-9 or caspase-3 after stimulation of apoptosis with staurosporine. However, inhibition of GSK3 reduced apoptosis and apoptosome formation, including the recruitments of caspase-9 and XIAP to Apaf-1, in response to staurosporine treatment. Cell free measurements of apoptosome-induced caspase-3 activation demonstrated that GSK3 acts upstream of the apoptosome to facilitate intrinsic apoptotic signaling. This facilitation was blocked by overexpression of XIAP. These findings indicate that the RING domain of XIAP (and probably cIAP-1 and cIAP-2) associates with GSK3, GSK3 acts upstream of the apoptosome to promote intrinsic apoptosis, and the association between XIAP and GSK3 may block the pro-apoptotic function of GSK3.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Mianen
authors.initials: M
authors.lastname: Sun
authors.forename: Gordon
authors.initials: G
authors.lastname: Meares
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D008094:Lithium / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013347:Subcellular Fractions / Q000737:chemistry; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein; D008094:Lithium; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020169:Caspases
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