Abstract
The nuclear receptor coactivator RAC3 plays important roles in many biological processes and tumorigenesis. We found that RAC3 is over-expressed in human chronic myeloid leukemia cells K562, which are normally resistant to TRAIL-induced apoptosis. RAC3 down-regulation by siRNA rendered these cells sensitive to TRAIL-induced cell death. In addition to the up-regulation of TRAIL receptors, the process involves Bid, caspases and PARP activation, loss of mitochondrial membrane potential, and release of AIF, cytochrome c and Smac/DIABLO to the cytoplasm. We conclude that RAC3 is required for TRAIL resistance and that this anti-apoptotic function is independent of its role in hormone receptor signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis* / genetics
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BH3 Interacting Domain Death Agonist Protein / metabolism
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Caspases / metabolism
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Cell Line, Tumor
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Down-Regulation
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Mitochondria / metabolism
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Nuclear Receptor Coactivator 3
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Poly(ADP-ribose) Polymerases / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Up-Regulation
Substances
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BH3 Interacting Domain Death Agonist Protein
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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RNA, Small Interfering
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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Transcription Factors
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Nuclear Receptor Coactivator 3
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Poly(ADP-ribose) Polymerases
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Caspases