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

Oncogene volume 31, pages 1311–1322 (2012)Cite this article

Abstract

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.

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Acknowledgements

We grateful to Dr Juha Klefstrom (University of Helsinki, Finland) and Dr Xiaolu Yang (University of Pennsylvania) for the kind gifts of pC4M-Fv2E-caspase-8 and the pC4M-Fv2E-caspase-8 C-A mutant and Mian Wu (University of Science and Technology of China, China) for the pGBKT7-FADD plasmid. The ARGENT Regulated Homodimerization Kit was kindly provided by ARIAD Pharmaceuticals (www.ariad.com/regulationkits). This work was supported in part by the National Natural Sciences Foundation of China (No. 30970921) and the National High-tech Research and Development program of China 973-projects (2011CB5004102).

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  1. Department of Neurobiology, Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Disease and School of Life Sciences, University of Science & Technology of China, Chinese Academy of Sciences, Hefei, Anhui, PR China

    K Fu, H Ren, Y Wang, E Fei, H Wang & G Wang

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Correspondence to G Wang.

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Fu, K., Ren, H., Wang, Y. et al. DJ-1 inhibits TRAIL-induced apoptosis by blocking pro-caspase-8 recruitment to FADD. Oncogene 31, 1311–1322 (2012). https://doi.org/10.1038/onc.2011.315

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