Activation of the NF-kappaB pathway by caspase 8 and its homologs.
Caspase 8 is the most proximal caspase in the caspase cascade and has been known for its role in the mediation of cell death by various death receptors belonging to the TNFR family. We have discovered that Caspase 8 can activate the NF-kappaB pathway independent of its activity as a pro-apoptotic protease. This property is localized to its N-terminal prodomain, which contains two homologous death effector domains (DEDs). Caspase 10 and MRIT, two DEDs-containing homologs of Caspase 8, can similarly activate the NF-kappaB pathway. Dominant-negative mutants of the Caspase 8 prodomain can block NF-kappaB induced by Caspase 8, FADD and several death receptors belonging to the TNFR family. Caspase 8 can interact with multiple proteins known to be involved in the activation of the NF-kappaB pathway, including the serine-threonine kinases RIP, NIK, IKK1 and IKK2. Thus, DEDs-containing caspases and caspase homolog(s) may have functions beyond their known role in the mediation of cell death. Oncogene (2000) 19, 4451 - 4460.
Chaudhary
P M
PM
Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas, TX 75390-8593, USA.
Eby
M T
MT
Jasmin
A
A
Kumar
A
A
Liu
L
L
Hood
L
L
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D029681:Arabidopsis Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D014764:Viral Proteins; D000097782:NF-kappaB-Inducing Kinase
D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; D029681:Arabidopsis Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D015853:Cysteine Proteinase Inhibitors; D044943:Fatty Acid Desaturases; D051550:I-kappa B Kinase; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D015843:Serpins; D047990:TNF Receptor-Associated Factor 1; D014764:Viral Proteins; D000097782:NF-kappaB-Inducing Kinase; C506386:CFLAR protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C074641:interleukin-1beta-converting enzyme inhibitor; C084083:Fad7 protein, Arabidopsis; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C506438:CASP10 protein, human