title: ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours.
abstract: 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: Grupo de Carcinogénesis Epitelial, Programa de Patología Molecular, CNIO-Spanish National Cancer Research Center, 28029 Madrid, Spain.
authors: M Luisa
authors: ML
authors: Campos
authors: Víctor J
authors: VJ
authors: Sánchez-Arévalo Lobo
authors: Annie
authors: A
authors: Rodolosse
authors: Cara J
authors: CJ
authors: Gottardi
authors: Andrea
authors: A
authors: Mafficini
authors: Stefania
authors: S
authors: Beghelli
authors: Maria
authors: M
authors: Scardoni
authors: Claudio
authors: C
authors: Bassi
authors: Aldo
authors: A
authors: Scarpa
authors: Francisco X
authors: FX
authors: Real
mesh_terms: D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000368:Aged; D002454:Cell Differentiation; D049109:Cell Proliferation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D046790:Pancreas, Exocrine / Q000378:metabolism* / Q000473:pathology; D010183:Pancreatic Ducts / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D055758:SOX9 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C495270:CTNNB1 protein, human; C411982:CTNNBIP1 protein, human; C527932:SOX9 protein, human; C084010:pancreatic and duodenal homeobox 1 protein; C062602:transcription factor PTF1