Corepressor CtBP and nuclear speckle protein Pnn/DRS differentially modulate transcription and splicing of the E-cadherin gene.
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.
Alpatov
Roman
R
Department of Anatomy and Cell Biology, University of Florida College of Medicine, 1600 SW Archer Road, Box 100235, Gainesville, FL 32610, USA.
Shi
Yujiang
Y
Munguba
Gustavo C
GC
Moghimi
Babak
B
Joo
Jeong-Hoon
JH
Bungert
Jorg
J
Sugrue
Stephen P
SP
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006388:Hemagglutinins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D015820:Cadherins; D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006388:Hemagglutinins; D009687:Nuclear Proteins; C102646:PNN protein, human; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D008156:Luciferases; D012319:RNA Polymerase II