The dependence receptor DCC (deleted in colorectal cancer) defines an alternative mechanism for caspase activation.
The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor/caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation.
Forcet
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Apoptosis/Differentiation Laboratory, Molecular and Cellular Genetic Center, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5534, University of Lyon, 69622 Villeurbanne, France.
Ye
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Granger
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Corset
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Shin
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Bredesen
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Mehlen
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P
D017209:Apoptosis; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002461:Cell Line, Transformed; D015179:Colorectal Neoplasms; D000075389:DCC Receptor; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D006801:Humans; D011956:Receptors, Cell Surface; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases