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- Title
Death effector domain DEDa, a self-cleaved product of caspase-8/Mch5, translocates to the nucleus by binding to ERK1/2 and upregulates procaspase-8 expression via a p53-dependent mechanism.
- Authors
Zhan Yao; Shanshan Duan; Dezhi Hou; Heese, Klaus; Mian Wu
- Abstract
Activation of the apical caspase-8 is crucial to the extrinsic apoptotic pathway. Although the death effector domain (DED) of caspase-8 has been reported to be involved in death-inducing signaling complex formation, the detailed mechanism of how DED functions in regulating apoptosis remains largely unknown. Here, we demonstrate that the prodomain of the caspase-8/Mch5 can be further cleaved between two tandemly repeated DEDs (DEDa–DEDb) at the amino-acid residue Asp129 by caspase-8 itself. The DEDa fragment generated from the endogenous caspase-8 was detected in isolated nucleoli upon treatment with TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). Cleaved DEDa appears to translocate into the nucleus by association with extracellular signal-regulated protein kinases-1/2 (ERK1/2). Elimination of ERK1/2 expression by RNA interference resulted in a significant attenuation of nuclear entry of DEDa and reduced caspase-8-dependent apoptosis. In the nucleus, DEDa interacts with TOPORS, a p53 and topoisomerase I binding protein, and possibly displaces p53 from TOPORS, allowing p53 to stimulate caspase-8 gene expression. In summary, we postulate a positive feedback loop involving DEDa, which enables the continual replenishment of procaspase-8 during apoptosis.
- Subjects
CELL nuclei; APOPTOSIS; NECROSIS; PROTEIN kinases; RNA; GENE expression
- Publication
EMBO Journal, 2007, Vol 26, Issue 4, p1068
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7601571