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The M476W/Q482H mutation of procaspase-8 restored caspase-8-mediated apoptosis

Author:
Li, Ming, Le Wei,, Zhang, Xue-Mei, Zhang, Ying-Jun, Jiang, Jie, Liu, Pin-Yue
Source:
Biochemical and biophysical research communications 2019 v.514 no.3 pp. 653-658
ISSN:
0006-291X
Subject:
Western blotting, apoptosis, caspase-8, dimerization, drug therapy, gene overexpression, mutants, mutation, neoplasms, patients, proteins
Abstract:
Caspase-8 is an initiator of apoptotic signalling, and aberrations in procaspase-8 have been verified to be associated with malignant tumours. In previous studies, various procaspase-8 mutants were identified in AML patients, such as Q482H and M476W/Q482H mutations. The Q482H mutation can abolish caspase-8-mediated apoptosis by attenuating the dimerization of procaspase-8 protein monomers, causing AML patients carrying the Q482H mutation to develop resistance to chemotherapeutics. The patients with the M476W/Q482H mutation were sensitive to chemotherapy. Nevertheless, the underlying molecular mechanism is still unclear in regard to how the M476W/Q482H mutation restored caspase-8-mediated apoptosis. In this study, apoptosis was detected in the cells overexpressing the WT or mutant procaspase-8 with or without TRAIL treatment. Western blotting was devoted to detect the cleavage of procaspase-8 or the expression of proteins downstream in the apoptotic cascade and CO-IP was employed to analyze the dimerization of WT and mutant procaspase-8 proteins. Results demonstrated cells carrying the M476W/Q482H mutation restored caspase-8-mediated and TRAIL-induced apoptosis. The M476W/Q482H mutation recovered the dimerization of procaspase-8. Taken together, the M476W/Q482H mutation have restored caspase-8-mediated apoptosis resulting from the recovery of procaspase-8 dimerization.
Agid:
6428578