title: Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP.
abstract: The death receptor Fas transduces apoptotic death signaling mediated by caspases. In the present study, human hepatoma HepG2 cells showed the Fas-mediated apoptosis mediated by caspase, especially caspase 3, only in the presence of actinomycin D. Interestingly, cytosolic proteins extracted from intact HepG2 cells induced caspase 3 inactivation. Our results reveal that this inactivation was triggered by the direct inhibition of activated caspase 3 by IAP gene family ILP. In addition, a 53 kDa protein was co-immunoprecipitated with anti-human caspase 3 antibody from intact HepG2 cells. This protein was a complex-protein of procaspase 3 and the cell cycle regulator p21WAF1 (p21). P21 bound to only procaspase 3, but not to activated caspase 3. We also demonstrate that p21 protein-loaded HepG2 cells resist to Fas-mediated apoptosis even in the presence of actinomycin D. Here we report that caspase 3 inactivation for the resistance to Fas-mediated apoptosis is induced by a procaspase 3/p21 complex formation and direct inhibition of activated caspase 3 by ILP.
authors.affiliation: Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., Tokyo R&D Center, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutomi
authors.forename: K
authors.initials: K
authors.lastname: Akahane
authors.forename: T
authors.initials: T
authors.lastname: Araki
authors.forename: M
authors.initials: M
authors.lastname: Miura
mesh_terms: D000911:Antibodies, Monoclonal / Q000502:physiology; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D005810:Multigene Family; D011233:Precipitin Tests; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004792:Enzyme Precursors; D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases