Document Detail


ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours.
MedLine Citation:
PMID:  23339455     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The PTF1 (pancreas transcription factor 1) complex is a master regulator of differentiation of acinar cells, responsible for the production of digestive enzymes. In the adult pancreas, PTF1 contains two pancreas-restricted transcription factors: Ptf1a and Rbpjl. PTF1 recruits P/CAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] which acetylates Ptf1a and enhances its transcriptional activity. Using yeast two-hybrid screening, we identified ICAT (inhibitor of β-catenin and Tcf4) as a novel Ptf1a interactor. ICAT regulates the Wnt pathway and cell proliferation. We validated and mapped the ICAT-Ptf1a interaction in vitro and in vivo. We demonstrated that, following its overexpression in acinar tumour cells, ICAT regulates negatively PTF1 activity in vitro and in vivo. This effect was independent of β-catenin and was mediated by direct binding to Ptf1a and displacement of P/CAF. ICAT also modulated the expression of Pdx1 and Sox9 in acinar tumour cells. ICAT overexpression reduced the interaction of Ptf1a with Rbpjl and P/CAF and impaired Ptf1a acetylation by P/CAF. ICAT did not affect the subcellular localization of Ptf1a. In human pancreas, ICAT displayed a cell-type-specific distribution; in acinar and endocrine cells, it was nuclear, whereas in ductal cells, it was cytoplasmic. In ductal adenocarcinomas, ICAT displayed mainly a nuclear or mixed distribution and the former was an independent marker of survival. ICAT regulates acinar differentiation and it does so through a novel Wnt pathway-independent mechanism that may contribute to pancreatic disease.
Authors:
M Luisa Campos; Víctor J Sánchez-Arévalo Lobo; Annie Rodolosse; Cara J Gottardi; Andrea Mafficini; Stefania Beghelli; Maria Scardoni; Claudio Bassi; Aldo Scarpa; Francisco X Real
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  451     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-15     Completed Date:  2013-05-31     Revised Date:  2013-10-28    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  395-405     Citation Subset:  IM    
Affiliation:
Grupo de Carcinogénesis Epitelial, Programa de Patología Molecular, CNIO-Spanish National Cancer Research Center, 28029 Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Acinar Cells / metabolism*,  pathology
Adenocarcinoma / genetics*,  metabolism,  mortality,  pathology
Aged
Cell Differentiation
Cell Proliferation
Electrophoretic Mobility Shift Assay
Female
Gene Expression Regulation, Neoplastic*
Homeodomain Proteins / genetics,  metabolism
Humans
Intracellular Signaling Peptides and Proteins / genetics*,  metabolism
Male
Middle Aged
Pancreas, Exocrine / metabolism*,  pathology
Pancreatic Ducts / metabolism,  pathology
Pancreatic Neoplasms / genetics*,  metabolism,  mortality,  pathology
Protein Binding
SOX9 Transcription Factor / genetics,  metabolism
Survival Analysis
Trans-Activators / genetics,  metabolism
Transcription Factors / genetics*,  metabolism
Two-Hybrid System Techniques
Wnt Signaling Pathway
beta Catenin / genetics,  metabolism
p300-CBP Transcription Factors / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 GM076561/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/CTNNB1 protein, human; 0/CTNNBIP1 protein, human; 0/Homeodomain Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/SOX9 Transcription Factor; 0/SOX9 protein, human; 0/Trans-Activators; 0/Transcription Factors; 0/beta Catenin; 0/pancreatic and duodenal homeobox 1 protein; 0/transcription factor PTF1; EC 2.3.1.48/p300-CBP Transcription Factors; EC 2.3.1.48/p300-CBP-associated factor
Comments/Corrections
Erratum In:
Biochem J. 2013 Jul 1;453(1):154

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