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lüll Role of Smac in cephalostatin-induced cell death Rudy A; Lopez-Anton N; Barth N; Pettit GR; Dirsch VM; Schulze-Osthoff K; Rehm M; Prehn JH; Vogler M; Fulda S; Vollmar AMCell Death Differ 2008[Dec]; 15 (12): 1930-40Cephalostatin 1 is a natural compound isolated from a marine worm that induces apoptosis in tumor cells via an apoptosome-independent but caspase-9-dependent pathway and through an endoplasmic reticulum stress response that is accompanied by caspase-4 activation. Here, we show that cephalostatin evokes mitochondrial Smac (second mitochondria-derived activator of caspases) but not cytochrome c release in various carcinoma cell lines. We also show that Smac is critically involved in caspase-9 activation as evidenced by gene silencing experiments. Remarkably, caspase-2 appears to be a major target for cephalostatin-induced cytosolic Smac. Using biochemical and genetic inhibition experiments, we demonstrate that caspase-2 participates in the apoptotic machinery induced by cephalostatin. Cephalostatin-activated caspase-2 appears to act as initiator caspase and is not involved in the activation of caspase-9. Importantly, experiments immunoprecipitating PIDD (p53-induced protein with a DD), RAIDD (RIP-associated ICH-1/CED-3-homologous protein with DD) and caspase-2 identify cephalostatin as an experimental drug that induces the formation of the PIDDosome. The bis-steroid cephalostatin proves to be both a helpful tool to investigate apoptotic signaling and a promising chemotherapeutic agent.|Apoptosis Regulatory Proteins[MESH]|Calpain/metabolism[MESH]|Carrier Proteins/metabolism[MESH]|Caspase 2/metabolism[MESH]|Caspase 9/metabolism[MESH]|Cell Death/drug effects[MESH]|Cytochromes c/metabolism[MESH]|Death Domain Receptor Signaling Adaptor Proteins[MESH]|Enzyme Activation/drug effects[MESH]|Gene Silencing/drug effects[MESH]|Humans[MESH]|Intracellular Signaling Peptides and Proteins/*metabolism[MESH]|JNK Mitogen-Activated Protein Kinases/metabolism[MESH]|Jurkat Cells[MESH]|Mitochondrial Proteins/*metabolism[MESH]|Phenazines/*pharmacology[MESH]|Proto-Oncogene Proteins c-bcl-2/metabolism[MESH]|Signal Transduction/drug effects[MESH]|Spiro Compounds/*pharmacology[MESH]|Steroids/*pharmacology[MESH] |