Abstract
CtBP is a transcriptional corepressor with tumorigenic potential that targets the promoter of the tumor suppressor gene E-cadherin. Pnn/DRS (Pnn) is a "nuclear speckle"-associated protein involved in mRNA processing as well as transcriptional regulation of E-cadherin via its binding to CtBP. Here, we show that CtBP can recruit Pnn to CtBP-associated complexes, resulting in Pnn-dependent chromatin remodeling at the E-cadherin promoter. In addition, CtBP and Pnn can differentially modulate E-cadherin mRNA splicing, with polymerase II serving as an interface in this event. Therefore, the Pnn/CtBP functional interplay represents a novel mechanism linking the corepressor CtBP and Pnn to the transcription-coupled mRNA splicing of a major tumor suppressor gene. Our findings implicate the existence of the molecular switches involved in tumorigenesis, which coordinate promoter-specific events and mRNA processing, by serving as bridging elements between the regulatory complexes both at gene promoters and within the mRNA splicing machineries.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alcohol Oxidoreductases / genetics
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Alcohol Oxidoreductases / metabolism*
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Cadherins / genetics*
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Line
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Chromatin Assembly and Disassembly
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Chromatin Immunoprecipitation
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DNA, Complementary
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation
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Genes, Reporter
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Genetic Vectors
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Green Fluorescent Proteins / metabolism
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HeLa Cells
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Hemagglutinins / metabolism
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Humans
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Kidney / cytology
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Luciferases / metabolism
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Models, Biological
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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RNA Interference
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RNA Polymerase II / metabolism
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RNA Splicing*
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins / metabolism
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Transcription, Genetic*
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Transfection
Substances
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Cadherins
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Cell Adhesion Molecules
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DNA, Complementary
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DNA-Binding Proteins
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Hemagglutinins
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Nuclear Proteins
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PNN protein, human
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RNA, Messenger
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Recombinant Fusion Proteins
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Repressor Proteins
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Green Fluorescent Proteins
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Alcohol Oxidoreductases
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C-terminal binding protein
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Luciferases
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RNA Polymerase II