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

Titlebeta-Catenin induces T-cell transformation by promoting genomic instability
Authors
KeywordsAnimals
Apoptosis
Base Sequence
Cell Survival
DNA Breaks, Double-Stranded
DNA Methylation
DNA Repair
Disease Models, Animal
Genes, RAG-1/genetics
*Genomic Instability
Hepatocyte Nuclear Factor 1-alpha
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
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
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.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectAnimals-
dc.subjectApoptosis-
dc.subjectBase Sequence-
dc.subjectCell Survival-
dc.subjectDNA Breaks, Double-Stranded-
dc.subjectDNA Methylation-
dc.subjectDNA Repair-
dc.subjectDisease Models, Animal-
dc.subjectGenes, RAG-1/genetics-
dc.subject*Genomic Instability-
dc.subjectHepatocyte Nuclear Factor 1-alpha-
dc.titlebeta-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.volume111-
dc.identifier.issue1-
dc.identifier.spage391-
dc.identifier.epage396-
dc.identifier.isiWOS:000329350700095-
dc.publisher.placeUnited States-

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