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Article: β-Catenin induces T-cell transformation by promoting genomic instability

Titleβ-Catenin induces T-cell transformation by promoting genomic instability
Authors
KeywordsBeta-catenin/Tcf-1
DNA recombination Tcf7
Ctnnb1
Issue Date2014
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2014, v. 111 n. 1, p. 391-396 How to Cite?
AbstractDeregulated activation of β-catenin in cancer has been correlated with genomic instability. During thymocyte development, β-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human TALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated β-catenin promoted an antiapoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.
Persistent Identifierhttp://hdl.handle.net/10722/219918
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDose, M-
dc.contributor.authorEmmanuel, AO-
dc.contributor.authorChaumeil, J-
dc.contributor.authorZhang, J-
dc.contributor.authorSun, T-
dc.contributor.authorGermar, K-
dc.contributor.authorAghajani, K-
dc.contributor.authorDavis, EM-
dc.contributor.authorKeerthivasan, S-
dc.contributor.authorBredemeyer, AL-
dc.contributor.authorSleckman, BP-
dc.contributor.authorRosen, ST-
dc.contributor.authorSkok, JA-
dc.contributor.authorLe Beau, MM-
dc.contributor.authorGeorgopoulos, K-
dc.contributor.authorGounari, F-
dc.date.accessioned2015-10-02T08:41:41Z-
dc.date.available2015-10-02T08:41:41Z-
dc.date.issued2014-
dc.identifier.citationProceedings of the National Academy of Sciences, 2014, v. 111 n. 1, p. 391-396-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/219918-
dc.description.abstractDeregulated activation of β-catenin in cancer has been correlated with genomic instability. During thymocyte development, β-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of β-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human TALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated β-catenin promoted an antiapoptosis gene expression profile. Thus, activated β-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.subjectBeta-catenin/Tcf-1-
dc.subjectDNA recombination Tcf7-
dc.subjectCtnnb1-
dc.titleβ-Catenin induces T-cell transformation by promoting genomic instability-
dc.typeArticle-
dc.identifier.emailZhang, J: jzhang1@hku.hk-
dc.identifier.authorityZhang, J=rp01713-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1315752111-
dc.identifier.pmid24371308-
dc.identifier.pmcidPMC3890837-
dc.identifier.scopuseid_2-s2.0-84891934864-
dc.identifier.hkuros291161-
dc.identifier.volume111-
dc.identifier.issue1-
dc.identifier.spage391-
dc.identifier.epage396-
dc.identifier.isiWOS:000329350700095-
dc.publisher.placeUnited States-
dc.identifier.issnl0027-8424-

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