ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours

M. Luisa Campos, Víctor J. Sánchez-Arévalo Lobo, Annie Rodolosse, Cara Gottardi, Andrea Mafficini, Stefania Beghelli, Maria Scardoni, Claudio Bassi, Aldo Scarpa, Francisco X. Real*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)395-405
Number of pages11
JournalBiochemical Journal
Volume451
Issue number3
DOIs
Publication statusPublished - May 1 2013

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Keywords

  • Cancer
  • Differentiation
  • Inhibitor of β-catenin and Tcf4 (ICAT)
  • P300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor (P/CAF)
  • Pancreas
  • Ptf1a

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Campos, M. L., Sánchez-Arévalo Lobo, V. J., Rodolosse, A., Gottardi, C., Mafficini, A., Beghelli, S., ... Real, F. X. (2013). ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. Biochemical Journal, 451(3), 395-405. https://doi.org/10.1042/BJ20120873