title: Distinctive effects of the cellular inhibitor of apoptosis protein c-IAP2 through stabilization by XIAP in glioblastoma multiforme cells.
abstract: Inhibitor of apoptosis proteins (IAPs) are extensively involved in NFκB signaling pathways. Regulation of c-IAP2 turnover by other proteins was investigated in glioblastoma multiforme (GBM) cells in the present study. When overexpressed, X-linked IAP (XIAP) enhanced expression of ectopic c-IAP2, but not c-IAP1, and endogenous c-IAP2 levels were reduced once XIAP expression was silenced. TNFα stimulation substantially increased c-IAP2 expression, and this upregulation was impaired by suppression of XIAP. Similarly, when XIAP was limiting due to severe hypoxic conditions, c-IAP2 levels were downregulated. These data together indicate that XIAP is an important regulator responsible for stabilization of c-IAP2 levels under different conditions. Protein interactions occur through binding of BIR2 and BIR3 domains of c-IAP2 with the RING finger of XIAP. XIAP inhibition of c-IAP2 auto-degradation was dependent on this physical interaction, and it was independent of XIAP E3 ligase activity. Global c-IAP2 ubiquitination was not affected by XIAP, although c-IAP2 levels were significantly increased. A CARD-RING-containing fragment of c-IAP2 was found to target XIAP for proteasome-independent degradation, but it was unable to sensitize GBM cells to chemo-reagents. The XIAP-stabilized c-IAP2 was found to enhance IκB-α phosphorylation on serines 32 and 36, and to antagonize XIAP-induced increase in mature Smac and Bcl10. Taken together, our data identify a distinctive role of c-IAP2 as stabilizer of XIAP, which is likely involved in regulation of NFκB activation and apoptosis in GBM cells.
authors.affiliation: Department of Radiation Oncology; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Cooke
authors.affiliation: Departments of Pathology and Internal Medicine and Comprehensive Cancer Center; University of Michigan; Ann Arbor, MI USA.
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
authors.affiliation: Department of Cancer Biology and the Abramson Family Cancer Research Institute; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Radiation Oncology; Perelman School of Medicine; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Jay F
authors.initials: JF
authors.lastname: Dorsey
mesh_terms: D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D054829:RING Finger Domains; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054875:Ubiquitination; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human
keywords: Bcl10; IκB-α; TNFα; XIAP; anoxia; auto-degradation; c-IAP2; glioblastoma multiforme cell lines; mature Smac