Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.

<h4>Background</h4>The transcription factor Tcfap2c has been demonstrated to be essential for various processes during mammalian development. It has been found to be upregulated in various undifferentiated tumors and is implicated with poor prognosis. Tcfap2c is reported to impinge on ce...

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Autores principales:	Daniel Holl, Peter Kuckenberg, Tatiana Woynecki, Angela Egert, Astrid Becker, Sebastian Huss, Dirk Stabenow, Andreas Zimmer, Percy Knolle, René Tolba, Hans-Peter Fischer, Hubert Schorle
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/173b8efce5f548cc942fd9a96206ad71
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spelling	oai:doaj.org-article:173b8efce5f548cc942fd9a96206ad712021-11-18T06:50:20ZTransgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.1932-620310.1371/journal.pone.0022034https://doaj.org/article/173b8efce5f548cc942fd9a96206ad712011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21779369/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The transcription factor Tcfap2c has been demonstrated to be essential for various processes during mammalian development. It has been found to be upregulated in various undifferentiated tumors and is implicated with poor prognosis. Tcfap2c is reported to impinge on cellular proliferation, differentiation and apoptosis. However, the physiological consequences of Tcfap2c-expression remain largely unknown.<h4>Methodology/principal findings</h4>Therefore we established a gain of function model to analyze the role of Tcfap2c in development and disease. Induction of the transgene led to robust expression in all tissues (except brain and testis) and lead to rapid mortality within 3-7 days. In the liver cellular proliferation and apoptosis was detected. Accumulation of microvesicular lipid droplets and breakdown of major hepatic metabolism pathways resulted in steatosis. Serum analysis showed a dramatic increase of enzymes indicative for hepatic failure. After induction of Tcfap2c we identified a set of 447 common genes, which are deregulated in both liver and primary hepatocyte culture. Further analysis showed a prominent repression of the cytochrome p450 system, PPARA, Lipin1 and Lipin2. These data indicate that in the liver Tcfap2c represses pathways, which are responsible for fatty acid metabolism. In the intestine, Tcfap2c expression resulted in expansion of Sox9 positive and proliferative active epithelial progenitor cells resulting in dysplastic growth of mucosal crypt cells and loss of differentiated mucosa.<h4>Conclusions</h4>The transgenic mice show that ectopic expression of Tcfap2c is not tolerated. Due to the phenotype observed, iTcfap2c-mice represent a model system to study liver failure. In intestine, Tcfap2c induced cellular hyperplasia and suppressed terminal differentiation indicating that Tcfap2c serves as a repressor of differentiation and inducer of proliferation. This might be achieved by the Tcfap2c mediated activation of Sox9 known to be expressed in intestinal and hepatic stem/progenitor cell populations.Daniel HollPeter KuckenbergTatiana WoyneckiAngela EgertAstrid BeckerSebastian HussDirk StabenowAndreas ZimmerPercy KnolleRené TolbaHans-Peter FischerHubert SchorlePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e22034 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daniel Holl Peter Kuckenberg Tatiana Woynecki Angela Egert Astrid Becker Sebastian Huss Dirk Stabenow Andreas Zimmer Percy Knolle René Tolba Hans-Peter Fischer Hubert Schorle Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
description	<h4>Background</h4>The transcription factor Tcfap2c has been demonstrated to be essential for various processes during mammalian development. It has been found to be upregulated in various undifferentiated tumors and is implicated with poor prognosis. Tcfap2c is reported to impinge on cellular proliferation, differentiation and apoptosis. However, the physiological consequences of Tcfap2c-expression remain largely unknown.<h4>Methodology/principal findings</h4>Therefore we established a gain of function model to analyze the role of Tcfap2c in development and disease. Induction of the transgene led to robust expression in all tissues (except brain and testis) and lead to rapid mortality within 3-7 days. In the liver cellular proliferation and apoptosis was detected. Accumulation of microvesicular lipid droplets and breakdown of major hepatic metabolism pathways resulted in steatosis. Serum analysis showed a dramatic increase of enzymes indicative for hepatic failure. After induction of Tcfap2c we identified a set of 447 common genes, which are deregulated in both liver and primary hepatocyte culture. Further analysis showed a prominent repression of the cytochrome p450 system, PPARA, Lipin1 and Lipin2. These data indicate that in the liver Tcfap2c represses pathways, which are responsible for fatty acid metabolism. In the intestine, Tcfap2c expression resulted in expansion of Sox9 positive and proliferative active epithelial progenitor cells resulting in dysplastic growth of mucosal crypt cells and loss of differentiated mucosa.<h4>Conclusions</h4>The transgenic mice show that ectopic expression of Tcfap2c is not tolerated. Due to the phenotype observed, iTcfap2c-mice represent a model system to study liver failure. In intestine, Tcfap2c induced cellular hyperplasia and suppressed terminal differentiation indicating that Tcfap2c serves as a repressor of differentiation and inducer of proliferation. This might be achieved by the Tcfap2c mediated activation of Sox9 known to be expressed in intestinal and hepatic stem/progenitor cell populations.
format	article
author	Daniel Holl Peter Kuckenberg Tatiana Woynecki Angela Egert Astrid Becker Sebastian Huss Dirk Stabenow Andreas Zimmer Percy Knolle René Tolba Hans-Peter Fischer Hubert Schorle
author_facet	Daniel Holl Peter Kuckenberg Tatiana Woynecki Angela Egert Astrid Becker Sebastian Huss Dirk Stabenow Andreas Zimmer Percy Knolle René Tolba Hans-Peter Fischer Hubert Schorle
author_sort	Daniel Holl
title	Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
title_short	Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
title_full	Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
title_fullStr	Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
title_full_unstemmed	Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.
title_sort	transgenic overexpression of tcfap2c/ap-2gamma results in liver failure and intestinal dysplasia.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/173b8efce5f548cc942fd9a96206ad71
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Transgenic overexpression of Tcfap2c/AP-2gamma results in liver failure and intestinal dysplasia.

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