Multi-level interactions between the nuclear receptor TRα1 and the WNT effectors β-catenin/Tcf4 in the intestinal epithelium
Intestinal homeostasis results from complex cross-regulation of signaling pathways; their alteration induces intestinal tumorigenesis. Previously, we found that the thyroid hormone nuclear receptor TRα1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tu...
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| description | Intestinal homeostasis results from complex cross-regulation of signaling pathways; their alteration induces intestinal tumorigenesis. Previously, we found that the thyroid hormone nuclear receptor TRα1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tumorigenesis. Here, we investigated the mechanisms and implications of the cross-regulation between these two pathways in gut tumorigenesis in vivo and in vitro. We analyzed TRα1 and WNT target gene expression in healthy mucosae and tumors from mice overexpressing TRα1 in the intestinal epithelium in a WNT-activated genetic background (vil-TRα1/Apc mice). Interestingly, increased levels of β-catenin/Tcf4 complex in tumors from vil-TRα1/Apc mice blocked TRα1 transcriptional activity. This observation was confirmed in Caco2 cells, in which TRα1 functionality on a luciferase reporter-assay was reduced by the overexpression of β-catenin/Tcf4. Moreover, TRα1 physically interacted with β-catenin/Tcf4 in the nuclei of these cells. Using molecular approaches, we demonstrated that the binding of TRα1 to its DNA target sequences within the tumors was impaired, while it was newly recruited to WNT target genes. In conclusion, our observations strongly suggest that increased β-catenin/Tcf4 levels i) correlated with reduced TRα1 transcriptional activity on its target genes and, ii) were likely responsible for the shift of TRα1 binding on WNT targets. Together, these data suggest a novel mechanism for the tumor-promoting activity of the TRα1 nuclear receptor. |
| doi_str_mv | 10.1371/journal.pone.0034162 |
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Previously, we found that the thyroid hormone nuclear receptor TRα1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tumorigenesis. Here, we investigated the mechanisms and implications of the cross-regulation between these two pathways in gut tumorigenesis in vivo and in vitro. We analyzed TRα1 and WNT target gene expression in healthy mucosae and tumors from mice overexpressing TRα1 in the intestinal epithelium in a WNT-activated genetic background (vil-TRα1/Apc mice). Interestingly, increased levels of β-catenin/Tcf4 complex in tumors from vil-TRα1/Apc mice blocked TRα1 transcriptional activity. This observation was confirmed in Caco2 cells, in which TRα1 functionality on a luciferase reporter-assay was reduced by the overexpression of β-catenin/Tcf4. Moreover, TRα1 physically interacted with β-catenin/Tcf4 in the nuclei of these cells. Using molecular approaches, we demonstrated that the binding of TRα1 to its DNA target sequences within the tumors was impaired, while it was newly recruited to WNT target genes. In conclusion, our observations strongly suggest that increased β-catenin/Tcf4 levels i) correlated with reduced TRα1 transcriptional activity on its target genes and, ii) were likely responsible for the shift of TRα1 binding on WNT targets. Together, these data suggest a novel mechanism for the tumor-promoting activity of the TRα1 nuclear receptor.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034162</identifier><identifier>PMID: 22509275</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenomatous polyposis coli ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; beta Catenin - metabolism ; Binding ; Biochemistry, Molecular Biology ; Biology ; Caco-2 Cells ; Cell adhesion & migration ; Cell growth ; Cell Nucleus - metabolism ; Cell proliferation ; Chromatin - metabolism ; Colorectal cancer ; Deoxyribonucleic acid ; DNA ; Epithelium ; Gene expression ; Gene Expression Regulation ; Gene sequencing ; Genes ; Homeostasis ; Humans ; Intestinal Mucosa - cytology ; Intestinal Mucosa - metabolism ; Intestinal Mucosa - pathology ; Intestinal Neoplasms - pathology ; Intestine ; Life Sciences ; Ligands ; Medicine ; Metastasis ; Mice ; Molecular biology ; Nuclei ; Nuclei (cytology) ; Nucleotide sequence ; Phosphorylation ; Protein Binding ; Proteins ; Response Elements - genetics ; Rodents ; Signaling ; Small intestine ; Thyroid ; Thyroid gland ; Thyroid Hormone Receptors alpha - metabolism ; Transcription ; Transcription Factor 4 ; Transcription factors ; Transcription, Genetic ; Tumorigenesis ; Tumors ; Wnt protein ; Wnt3A Protein - metabolism ; β-Catenin</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34162-e34162</ispartof><rights>2012 Sirakov et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Sirakov et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c560t-5d9606b6714065411197e78bf3f6b479b1ea5e86e12fc09804aa7f6c1134774b3</citedby><cites>FETCH-LOGICAL-c560t-5d9606b6714065411197e78bf3f6b479b1ea5e86e12fc09804aa7f6c1134774b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317923/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317923/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22509275$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00720092$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Sirakov, Maria</creatorcontrib><creatorcontrib>Skah, Seham</creatorcontrib><creatorcontrib>Lone, Imtiaz Nisar</creatorcontrib><creatorcontrib>Nadjar, Julien</creatorcontrib><creatorcontrib>Angelov, Dimitar</creatorcontrib><creatorcontrib>Plateroti, Michelina</creatorcontrib><title>Multi-level interactions between the nuclear receptor TRα1 and the WNT effectors β-catenin/Tcf4 in the intestinal epithelium</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Intestinal homeostasis results from complex cross-regulation of signaling pathways; their alteration induces intestinal tumorigenesis. Previously, we found that the thyroid hormone nuclear receptor TRα1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tumorigenesis. Here, we investigated the mechanisms and implications of the cross-regulation between these two pathways in gut tumorigenesis in vivo and in vitro. We analyzed TRα1 and WNT target gene expression in healthy mucosae and tumors from mice overexpressing TRα1 in the intestinal epithelium in a WNT-activated genetic background (vil-TRα1/Apc mice). Interestingly, increased levels of β-catenin/Tcf4 complex in tumors from vil-TRα1/Apc mice blocked TRα1 transcriptional activity. This observation was confirmed in Caco2 cells, in which TRα1 functionality on a luciferase reporter-assay was reduced by the overexpression of β-catenin/Tcf4. Moreover, TRα1 physically interacted with β-catenin/Tcf4 in the nuclei of these cells. Using molecular approaches, we demonstrated that the binding of TRα1 to its DNA target sequences within the tumors was impaired, while it was newly recruited to WNT target genes. In conclusion, our observations strongly suggest that increased β-catenin/Tcf4 levels i) correlated with reduced TRα1 transcriptional activity on its target genes and, ii) were likely responsible for the shift of TRα1 binding on WNT targets. Together, these data suggest a novel mechanism for the tumor-promoting activity of the TRα1 nuclear receptor.</description><subject>Adenomatous polyposis coli</subject><subject>Animals</subject><subject>Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism</subject><subject>beta Catenin - metabolism</subject><subject>Binding</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biology</subject><subject>Caco-2 Cells</subject><subject>Cell adhesion & migration</subject><subject>Cell growth</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell proliferation</subject><subject>Chromatin - metabolism</subject><subject>Colorectal cancer</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Epithelium</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestinal Mucosa - pathology</subject><subject>Intestinal Neoplasms - pathology</subject><subject>Intestine</subject><subject>Life Sciences</subject><subject>Ligands</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Molecular biology</subject><subject>Nuclei</subject><subject>Nuclei (cytology)</subject><subject>Nucleotide sequence</subject><subject>Phosphorylation</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Response Elements - genetics</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Small intestine</subject><subject>Thyroid</subject><subject>Thyroid gland</subject><subject>Thyroid Hormone Receptors alpha - metabolism</subject><subject>Transcription</subject><subject>Transcription Factor 4</subject><subject>Transcription factors</subject><subject>Transcription, Genetic</subject><subject>Tumorigenesis</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Wnt3A Protein - 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metabolism</topic><topic>beta Catenin - metabolism</topic><topic>Binding</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biology</topic><topic>Caco-2 Cells</topic><topic>Cell adhesion & migration</topic><topic>Cell growth</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell proliferation</topic><topic>Chromatin - metabolism</topic><topic>Colorectal cancer</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Epithelium</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gene sequencing</topic><topic>Genes</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestinal Mucosa - pathology</topic><topic>Intestinal Neoplasms - pathology</topic><topic>Intestine</topic><topic>Life Sciences</topic><topic>Ligands</topic><topic>Medicine</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Molecular biology</topic><topic>Nuclei</topic><topic>Nuclei (cytology)</topic><topic>Nucleotide sequence</topic><topic>Phosphorylation</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Response Elements - 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Previously, we found that the thyroid hormone nuclear receptor TRα1 activates and synergizes with the WNT pathway, inducing crypt cell proliferation and promoting tumorigenesis. Here, we investigated the mechanisms and implications of the cross-regulation between these two pathways in gut tumorigenesis in vivo and in vitro. We analyzed TRα1 and WNT target gene expression in healthy mucosae and tumors from mice overexpressing TRα1 in the intestinal epithelium in a WNT-activated genetic background (vil-TRα1/Apc mice). Interestingly, increased levels of β-catenin/Tcf4 complex in tumors from vil-TRα1/Apc mice blocked TRα1 transcriptional activity. This observation was confirmed in Caco2 cells, in which TRα1 functionality on a luciferase reporter-assay was reduced by the overexpression of β-catenin/Tcf4. Moreover, TRα1 physically interacted with β-catenin/Tcf4 in the nuclei of these cells. Using molecular approaches, we demonstrated that the binding of TRα1 to its DNA target sequences within the tumors was impaired, while it was newly recruited to WNT target genes. In conclusion, our observations strongly suggest that increased β-catenin/Tcf4 levels i) correlated with reduced TRα1 transcriptional activity on its target genes and, ii) were likely responsible for the shift of TRα1 binding on WNT targets. Together, these data suggest a novel mechanism for the tumor-promoting activity of the TRα1 nuclear receptor.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22509275</pmid><doi>10.1371/journal.pone.0034162</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| subjects | Adenomatous polyposis coli Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism beta Catenin - metabolism Binding Biochemistry, Molecular Biology Biology Caco-2 Cells Cell adhesion & migration Cell growth Cell Nucleus - metabolism Cell proliferation Chromatin - metabolism Colorectal cancer Deoxyribonucleic acid DNA Epithelium Gene expression Gene Expression Regulation Gene sequencing Genes Homeostasis Humans Intestinal Mucosa - cytology Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Intestinal Neoplasms - pathology Intestine Life Sciences Ligands Medicine Metastasis Mice Molecular biology Nuclei Nuclei (cytology) Nucleotide sequence Phosphorylation Protein Binding Proteins Response Elements - genetics Rodents Signaling Small intestine Thyroid Thyroid gland Thyroid Hormone Receptors alpha - metabolism Transcription Transcription Factor 4 Transcription factors Transcription, Genetic Tumorigenesis Tumors Wnt protein Wnt3A Protein - metabolism β-Catenin |
| title | Multi-level interactions between the nuclear receptor TRα1 and the WNT effectors β-catenin/Tcf4 in the intestinal epithelium |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T09%3A32%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multi-level%20interactions%20between%20the%20nuclear%20receptor%20TR%CE%B11%20and%20the%20WNT%20effectors%20%CE%B2-catenin/Tcf4%20in%20the%20intestinal%20epithelium&rft.jtitle=PloS%20one&rft.au=Sirakov,%20Maria&rft.date=2012-04-03&rft.volume=7&rft.issue=4&rft.spage=e34162&rft.epage=e34162&rft.pages=e34162-e34162&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0034162&rft_dat=%3Cproquest_plos_%3E1002530458%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1344197522&rft_id=info:pmid/22509275&rft_doaj_id=oai_doaj_org_article_0c133a07de4848de9278e11ecfed1173&rfr_iscdi=true |