Abstract
Caspases play a central role in apoptosis, a well-studied pathway of programmed cell death. Other programs of death potentially involving necrosis and autophagy may exist, but their relation to apoptosis and mechanisms of regulation remains unclear. We define a new molecular pathway in which activation of the receptor-interacting protein (a serine-threonine kinase) and Jun amino-terminal kinase induced cell death with the morphology of autophagy. Autophagic death required the genes ATG7 and beclin 1 and was induced by caspase-8 inhibition. Clinical therapies involving caspase inhibitors may arrest apoptosis but also have the unanticipated effect of promoting autophagic cell death.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Apoptosis Regulatory Proteins
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Autophagy*
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Beclin-1
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Caspase 8
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Caspase Inhibitors*
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Caspases / genetics
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Caspases / metabolism*
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Cell Death*
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Cell Line
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Cells, Cultured
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Humans
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 7
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MAP Kinase Signaling System
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Membrane Proteins
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Mice
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism*
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RNA Interference
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Receptor-Interacting Protein Serine-Threonine Kinases
Substances
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Amino Acid Chloromethyl Ketones
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Becn1 protein, mouse
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Caspase Inhibitors
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Membrane Proteins
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Proteins
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benzyloxycarbonyl-valyl-alanyl-(methyl)aspartic acid fluoromethyl ketone
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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Ripk1 protein, mouse
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 7
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MAP2K7 protein, human
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Map2k7 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8
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Caspases