Brg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine
Identifieur interne : 003B65 ( Main/Exploration ); précédent : 003B64; suivant : 003B66Brg1 Loss Attenuates Aberrant Wnt-Signalling and Prevents Wnt-Dependent Tumourigenesis in the Murine Small Intestine
Auteurs : Aliaksei Z. Holik [Royaume-Uni, Australie] ; Madeleine Young [Royaume-Uni] ; Joanna Krzystyniak [Royaume-Uni] ; Geraint T. Williams [Royaume-Uni] ; Daniel Metzger [France] ; Boris Y. Shorning [Royaume-Uni] ; Alan R. Clarke [Royaume-Uni]Source :
- PLoS Genetics [ 1553-7390 ] ; 2014.
Descripteurs français
- KwdFr :
- Adénomes (anatomopathologie), Adénomes (génétique), Animaux, Carcinogenèse (génétique), Cellules souches tumorales (anatomopathologie), Cellules souches tumorales (métabolisme), Facteurs de transcription (biosynthèse), Facteurs de transcription (génétique), Helicase (biosynthèse), Helicase (génétique), Humains, Intestin grêle (anatomopathologie), Intestin grêle (métabolisme), Muqueuse intestinale (anatomopathologie), Muqueuse intestinale (métabolisme), Protéines nucléaires (biosynthèse), Protéines nucléaires (génétique), Régulation de l'expression des gènes tumoraux, Souris, Voie de signalisation Wnt (génétique).
- MESH :
- anatomopathologie : Adénomes, Cellules souches tumorales, Intestin grêle, Muqueuse intestinale.
- biosynthèse : Facteurs de transcription, Helicase, Protéines nucléaires.
- génétique : Adénomes, Carcinogenèse, Facteurs de transcription, Helicase, Protéines nucléaires, Voie de signalisation Wnt.
- métabolisme : Cellules souches tumorales, Intestin grêle, Muqueuse intestinale.
- Animaux, Humains, Régulation de l'expression des gènes tumoraux, Souris.
English descriptors
- KwdEn :
- Adenoma (genetics), Adenoma (pathology), Animals, Carcinogenesis (genetics), DNA Helicases (biosynthesis), DNA Helicases (genetics), Gene Expression Regulation, Neoplastic, Humans, Intestinal Mucosa (metabolism), Intestinal Mucosa (pathology), Intestine, Small (metabolism), Intestine, Small (pathology), Mice, Neoplastic Stem Cells (metabolism), Neoplastic Stem Cells (pathology), Nuclear Proteins (biosynthesis), Nuclear Proteins (genetics), Transcription Factors (biosynthesis), Transcription Factors (genetics), Wnt Signaling Pathway (genetics).
- MESH :
- chemical , biosynthesis : DNA Helicases, Nuclear Proteins, Transcription Factors.
- genetics : Adenoma, Carcinogenesis, DNA Helicases, Nuclear Proteins, Transcription Factors, Wnt Signaling Pathway.
- metabolism : Intestinal Mucosa, Intestine, Small, Neoplastic Stem Cells.
- pathology : Adenoma, Intestinal Mucosa, Intestine, Small, Neoplastic Stem Cells.
- Animals, Gene Expression Regulation, Neoplastic, Humans, Mice.
Abstract
Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an
Url:
DOI: 10.1371/journal.pgen.1004453
PubMed: 25010414
PubMed Central: 4091792
Affiliations:
- Australie, France, Royaume-Uni
- Alsace (région administrative), Grand Est, Victoria (État)
- Melbourne, Strasbourg
- Université de Strasbourg
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Le document en format XML
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Shorning</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cardiff School of Biosciences, Cardiff University, Cardiff</wicri:regionArea><wicri:noRegion>Cardiff</wicri:noRegion></affiliation></author><author><name sortKey="Clarke, Alan R" sort="Clarke, Alan R" uniqKey="Clarke A" first="Alan R." last="Clarke">Alan R. Clarke</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cardiff School of Biosciences, Cardiff University, Cardiff</wicri:regionArea><wicri:noRegion>Cardiff</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenoma (genetics)</term><term>Adenoma (pathology)</term><term>Animals</term><term>Carcinogenesis (genetics)</term><term>DNA Helicases (biosynthesis)</term><term>DNA Helicases (genetics)</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Intestinal Mucosa (metabolism)</term><term>Intestinal Mucosa (pathology)</term><term>Intestine, Small (metabolism)</term><term>Intestine, Small (pathology)</term><term>Mice</term><term>Neoplastic Stem Cells (metabolism)</term><term>Neoplastic Stem Cells (pathology)</term><term>Nuclear Proteins (biosynthesis)</term><term>Nuclear Proteins (genetics)</term><term>Transcription Factors (biosynthesis)</term><term>Transcription Factors (genetics)</term><term>Wnt Signaling Pathway (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adénomes (anatomopathologie)</term><term>Adénomes (génétique)</term><term>Animaux</term><term>Carcinogenèse (génétique)</term><term>Cellules souches tumorales (anatomopathologie)</term><term>Cellules souches tumorales (métabolisme)</term><term>Facteurs de transcription (biosynthèse)</term><term>Facteurs de transcription (génétique)</term><term>Helicase (biosynthèse)</term><term>Helicase (génétique)</term><term>Humains</term><term>Intestin grêle (anatomopathologie)</term><term>Intestin grêle (métabolisme)</term><term>Muqueuse intestinale (anatomopathologie)</term><term>Muqueuse intestinale (métabolisme)</term><term>Protéines nucléaires (biosynthèse)</term><term>Protéines nucléaires (génétique)</term><term>Régulation de l'expression des gènes tumoraux</term><term>Souris</term><term>Voie de signalisation Wnt (génétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>DNA Helicases</term><term>Nuclear Proteins</term><term>Transcription Factors</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Adénomes</term><term>Cellules souches tumorales</term><term>Intestin grêle</term><term>Muqueuse intestinale</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Facteurs de transcription</term><term>Helicase</term><term>Protéines nucléaires</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Adenoma</term><term>Carcinogenesis</term><term>DNA Helicases</term><term>Nuclear Proteins</term><term>Transcription Factors</term><term>Wnt Signaling Pathway</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Adénomes</term><term>Carcinogenèse</term><term>Facteurs de transcription</term><term>Helicase</term><term>Protéines nucléaires</term><term>Voie de signalisation Wnt</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Intestinal Mucosa</term><term>Intestine, Small</term><term>Neoplastic Stem Cells</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cellules souches tumorales</term><term>Intestin grêle</term><term>Muqueuse intestinale</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Adenoma</term><term>Intestinal Mucosa</term><term>Intestine, Small</term><term>Neoplastic Stem Cells</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Gene Expression Regulation, Neoplastic</term><term>Humans</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Régulation de l'expression des gènes tumoraux</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Tumourigenesis within the intestine is potently driven by deregulation of the Wnt pathway, a process epigenetically regulated by the chromatin remodelling factor Brg1. We aimed to investigate this interdependency in an <italic>in vivo</italic> setting and assess the viability of Brg1 as a potential therapeutic target. Using a range of transgenic approaches, we deleted <italic>Brg1</italic> in the context of Wnt-activated murine small intestinal epithelium. Pan-epithelial loss of Brg1 using <italic>VillinCreER<sup>T2</sup></italic> and <italic>AhCreER<sup>T</sup></italic> transgenes attenuated expression of Wnt target genes, including a subset of stem cell-specific genes and suppressed Wnt-driven tumourigenesis improving animal survival. A similar increase in survival was observed when Wnt activation and Brg1 loss were restricted to the Lgr5 expressing intestinal stem cell population. We propose a mechanism whereby Brg1 function is required for aberrant Wnt signalling and ultimately for the maintenance of the tumour initiating cell compartment, such that loss of Brg1 in an Apc-deficient context suppresses adenoma formation. Our results highlight potential therapeutic value of targeting Brg1 and serve as a proof of concept that targeting the cells of origin of cancer may be of therapeutic relevance.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Giles, Rh" uniqKey="Giles R">RH Giles</name></author><author><name sortKey="Van Es, Jh" uniqKey="Van Es J">JH van Es</name></author><author><name sortKey="Clevers, H" uniqKey="Clevers H">H Clevers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gehrke, I" uniqKey="Gehrke I">I Gehrke</name></author><author><name sortKey="Gandhirajan, Rk" uniqKey="Gandhirajan R">RK Gandhirajan</name></author><author><name sortKey="Kreuzer, K A" uniqKey="Kreuzer K">K-A Kreuzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ellis, L" uniqKey="Ellis L">L Ellis</name></author><author><name sortKey="Atadja, Pw" uniqKey="Atadja P">PW 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Ritchie</name></author><author><name sortKey="Tavare, S" uniqKey="Tavare S">S Tavaré</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marsh, V" uniqKey="Marsh V">V Marsh</name></author><author><name sortKey="Winton, Dj" uniqKey="Winton D">DJ Winton</name></author><author><name sortKey="Williams, Gt" uniqKey="Williams G">GT Williams</name></author><author><name sortKey="Dubois, N" uniqKey="Dubois N">N Dubois</name></author><author><name sortKey="Trumpp, A" uniqKey="Trumpp A">A Trumpp</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sato, T" uniqKey="Sato T">T Sato</name></author><author><name sortKey="Vries, Rg" uniqKey="Vries R">RG Vries</name></author><author><name sortKey="Snippert, Hj" uniqKey="Snippert H">HJ Snippert</name></author><author><name sortKey="Van De Wetering, M" uniqKey="Van De Wetering M">M van de Wetering</name></author><author><name sortKey="Barker, N" uniqKey="Barker N">N Barker</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li></country><region><li>Alsace (région administrative)</li><li>Grand Est</li><li>Victoria (État)</li></region><settlement><li>Melbourne</li><li>Strasbourg</li></settlement><orgName><li>Université de Strasbourg</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Holik, Aliaksei Z" sort="Holik, Aliaksei Z" uniqKey="Holik A" first="Aliaksei Z." last="Holik">Aliaksei Z. Holik</name></noRegion><name sortKey="Clarke, Alan R" sort="Clarke, Alan R" uniqKey="Clarke A" first="Alan R." last="Clarke">Alan R. Clarke</name><name sortKey="Krzystyniak, Joanna" sort="Krzystyniak, Joanna" uniqKey="Krzystyniak J" first="Joanna" last="Krzystyniak">Joanna Krzystyniak</name><name sortKey="Shorning, Boris Y" sort="Shorning, Boris Y" uniqKey="Shorning B" first="Boris Y." last="Shorning">Boris Y. Shorning</name><name sortKey="Williams, Geraint T" sort="Williams, Geraint T" uniqKey="Williams G" first="Geraint T." last="Williams">Geraint T. Williams</name><name sortKey="Young, Madeleine" sort="Young, Madeleine" uniqKey="Young M" first="Madeleine" last="Young">Madeleine Young</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Holik, Aliaksei Z" sort="Holik, Aliaksei Z" uniqKey="Holik A" first="Aliaksei Z." last="Holik">Aliaksei Z. Holik</name></region></country><country name="France"><region name="Grand Est"><name sortKey="Metzger, Daniel" sort="Metzger, Daniel" uniqKey="Metzger D" first="Daniel" last="Metzger">Daniel Metzger</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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