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DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD.

Oncogene | Mar 8, 2012

http://www.ncbi.nlm.nih.gov/pubmed/21785459

DJ-1 was initially identified as an oncogene product involved in human tumorigenesis in cooperation with Ras. Increased DJ-1 expression is associated with tumorigenesis in many cancers, whereas the loss of DJ-1 function is linked to an autosomal recessive form of Parkinson's disease (PD). It has been reported that DJ-1 protects cells from TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. However, the mechanism by which DJ-1 is involved is still largely unknown. Here we show that DJ-1 inhibits TRAIL-induced apoptosis by blocking Fas-associated protein death domain (FADD)-mediated pro-caspase-8 activation. Wild-type DJ-1, but not the PD-associated mutant L166P, binds to FADD to inhibit the formation of the death-inducing signaling complex (DISC). DJ-1 competes with pro-caspase-8 to bind to FADD at the death effector domain, thereby repressing the recruitment and activation of pro-caspase-8 to the active form of caspase-8. Thus, our study suggests that DJ-1 protects against TRAIL-induced apoptosis through the regulation of DISC formation.

Pubmed ID: 21785459 RIS Download

Mesh terms: Apoptosis | Caspase 8 | Caspase Inhibitors | Cells, Cultured | Fas-Associated Death Domain Protein | Humans | Intracellular Signaling Peptides and Proteins | Oncogene Proteins | Protein Transport | RNA, Messenger | Receptors, TNF-Related Apoptosis-Inducing Ligand | TNF-Related Apoptosis-Inducing Ligand | Tumor Suppressor Protein p53

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