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 Citations (Scopus)

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
StatePublished - May 1 2013

Fingerprint

Catenins
Tumors
Display devices
Pancreas
Acinar Cells
Neoplasms
Transcription Factors
Wnt Signaling Pathway
Cells
Acetylation
Cyclic AMP Response Element-Binding Protein
Pancreatic Diseases
Endocrine Cells
Cell proliferation
Protein Binding
Yeast
Carrier Proteins
Screening
Adenocarcinoma
Yeasts

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
Campos, M. Luisa ; Sánchez-Arévalo Lobo, Víctor J. ; Rodolosse, Annie ; Gottardi, Cara ; Mafficini, Andrea ; Beghelli, Stefania ; Scardoni, Maria ; Bassi, Claudio ; Scarpa, Aldo ; Real, Francisco X. / ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. In: Biochemical Journal. 2013 ; Vol. 451, No. 3. pp. 395-405.
@article{937df1b7e8b04907b7d7322b6be78e2d,
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.",
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",
author = "Campos, {M. Luisa} and {S{\'a}nchez-Ar{\'e}valo Lobo}, {V{\'i}ctor J.} and Annie Rodolosse and Cara Gottardi and Andrea Mafficini and Stefania Beghelli and Maria Scardoni and Claudio Bassi and Aldo Scarpa and Real, {Francisco X.}",
year = "2013",
month = "5",
day = "1",
doi = "10.1042/BJ20120873",
language = "English (US)",
volume = "451",
pages = "395--405",
journal = "Biochemical Journal",
issn = "0264-6021",
publisher = "Portland Press Ltd.",
number = "3",

}

Campos, ML, Sánchez-Arévalo Lobo, VJ, Rodolosse, A, Gottardi, C, Mafficini, A, Beghelli, S, Scardoni, M, Bassi, C, Scarpa, A & Real, FX 2013, 'ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours', Biochemical Journal, vol. 451, no. 3, pp. 395-405. https://doi.org/10.1042/BJ20120873

ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours. / Campos, M. Luisa; Sánchez-Arévalo Lobo, Víctor J.; Rodolosse, Annie; Gottardi, Cara; Mafficini, Andrea; Beghelli, Stefania; Scardoni, Maria; Bassi, Claudio; Scarpa, Aldo; Real, Francisco X.

In: Biochemical Journal, Vol. 451, No. 3, 01.05.2013, p. 395-405.

Research output: Contribution to journalArticle

TY - JOUR

T1 - ICAT is a novel Ptf1a interactor that regulates pancreatic acinar differentiation and displays altered expression in tumours

AU - Campos, M. Luisa

AU - Sánchez-Arévalo Lobo, Víctor J.

AU - Rodolosse, Annie

AU - Gottardi, Cara

AU - Mafficini, Andrea

AU - Beghelli, Stefania

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Scarpa, Aldo

AU - Real, Francisco X.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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.

AB - 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.

KW - Cancer

KW - Differentiation

KW - Inhibitor of β-catenin and Tcf4 (ICAT)

KW - P300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor (P/CAF)

KW - Pancreas

KW - Ptf1a

UR - http://www.scopus.com/inward/record.url?scp=84876268223&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876268223&partnerID=8YFLogxK

U2 - 10.1042/BJ20120873

DO - 10.1042/BJ20120873

M3 - Article

VL - 451

SP - 395

EP - 405

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 3

ER -