Role of XIAP in NFkappaB activation
Date Issued
2011
Date
2011
Author(s)
Chiang, I-Hsuan
Abstract
X-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family. Previous studies reported that XIAP activates NF-κB by association with TAK1 which phosphorylates and activates IKK. The regulation of XIAP in stimulation through various physiological ligands for the activation of NF-κB, however, has not been confirmed. Previous study from our lab found that Notch intracellular domain (NICD) inhibits ubiquitination and degradation of XIAP. Other studies indicated that Notch can activate NF-κB. The specific aims of this study are to determine the role of XIAP in NF-κB activation induced by TNFα, T cell receptor (TCR) and Notch. We first established XIAP-knockdown and XIAP-overexpression DO11.10 T cell line. Upon stimulation with TNFα, the phosphorylation and degradation of IκBα, as well as p65 nucleus translocation, were not affected by knockdown and overexpression of XIAP. For the role of XIAP in TCR-induced NF-κB activation, XIAP deficiency reduced TCR-mediated phosphorylation of IKK and IκBα, p65 nucleus translocation, and κB promoter activation. Consistent with these results, XIAP overexpression increased the activation of NF-κB triggered by TCR. However, the activation of PKCθ and protein levels of Bcl10. But the phosphorylation of PKCθ and expression of Bcl10 proteins were not affected by XIAP knockdown or expression in TCR-stimulated DO11.10 T cells. For the role of XIAP in Notch-activated NF- κB, we found that knockdown of XIAP lead to decreased p65 nucleus translocation after Notch ligand stimulation. In addition, NICD formation and transcription of Notch target gene, dtx1, were also decreased.
Subjects
XIAP
NFkappa activation
Type
thesis
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