Abstract
The inhibitor of apoptosis (IAP) protein survivin is highly expressed in cancers, but not in normal differentiated tissues. TCF/beta-catenin signaling has been reported to participate in the regulation of survivin transcription in colon cancer. We have recently characterized ICG-001, a small molecule specific inhibitor of the beta-catenin/Creb-binding protein (CBP) interaction. Inhibition of the beta-catenin/CBP interaction represses a subset of TCF/beta-catenin-mediated transcription. ICG-001 potently inhibits survivin gene transcription and expression. ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis, which was rescued by overexpression of wild type but not mutant (C84A) survivin. Small interfering RNA and genetic reduction of CBP also decreased survivin expression. Chromatin immunoprecipitation assay confirmed that CBP is the crucial coactivator for TCF/beta-catenin-mediated survivin transcription. Furthermore, ICG-001-induced recruitment of p300 to the survivin promoter led to concomitant recruitment of SUMO-1, HDAC6 and PML proteins, which have been associated with transcriptional repression. These findings demonstrate that CBP and p300 play very distinct roles in survivin gene transcription.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Caspase 3
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Caspases / drug effects
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Caspases / metabolism
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Cell Line, Tumor
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Cytoskeletal Proteins / metabolism*
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E1A-Associated p300 Protein
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Female
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Gene Expression / drug effects
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Humans
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Immunoblotting
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Immunohistochemistry
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Inhibitor of Apoptosis Proteins
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Male
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Mice
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Microtubule-Associated Proteins / drug effects
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Models, Biological
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Neoplasm Proteins
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Neoplasms / metabolism
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Nuclear Proteins / metabolism*
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Pyrimidinones / pharmacology
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RNA, Small Interfering
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology*
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Survivin
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Trans-Activators / metabolism*
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Transcription, Genetic / genetics
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beta Catenin
Substances
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BIRC5 protein, human
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Bridged Bicyclo Compounds, Heterocyclic
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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Cytoskeletal Proteins
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ICG 001
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Nuclear Proteins
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Pyrimidinones
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RNA, Small Interfering
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Survivin
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Trans-Activators
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beta Catenin
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E1A-Associated p300 Protein
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Ep300 protein, mouse
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CASP3 protein, human
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Casp3 protein, mouse
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Caspase 3
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Caspases