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dc.contributor.authorChen, Peng-Chieh
dc.contributor.authorKuraguchi, Mari
dc.contributor.authorVelasquez, John
dc.contributor.authorWang, Yuxun
dc.contributor.authorYang, Kan
dc.contributor.authorEdwards, Robert R
dc.contributor.authorGillen, Dan
dc.contributor.authorEdelmann, Winfried
dc.contributor.authorKucherlapati, Raju
dc.contributor.authorLipkin, Steven M.
dc.date.accessioned2013-01-29T16:44:52Z
dc.date.issued2008
dc.identifier.citationChen, Peng-Chieh, Mari Kuraguchi, John Velasquez, Yuxun Wang, Kan Yang, Robert Edwards, Dan Gillen, Winfried Edelmann, Raju Kucherlapati, and Steven M. Lipkin. 2008. Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. PLoS Genetics 4(6): e1000092.en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10236036
dc.description.abstractDNA mismatch repair suppresses gastrointestinal tumorgenesis. Four mammalian E. coli MutL homologues heterodimerize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1. To understand the mechanistic contributions of MLH3 and PMS2 in gastrointestinal tumor suppression, we generated \(Mlh3^{−/−}\);\(Apc^{1638N}\) and \(Mlh3^{−/−}\);\(Pms2^{−/−}\);\(Apc^{1638N}\) (MPA) mice. Mlh3 nullizygosity significantly increased Apc frameshift mutations and tumor multiplicity. Combined Mlh3;Pms2 nullizygosity further increased Apc base-substitution mutations. The spectrum of MPA tumor mutations was distinct from that observed in \(Mlh1^{−/−}\);\(Apc^{1638N}\) mice, implicating the first potential role for MLH1/PMS1 in tumor suppression. Because Mlh3;Pms2 deficiency also increased gastrointestinal tumor progression, we used array-CGH to identify a recurrent tumor amplicon. This amplicon contained a previously uncharacterized Transducin enhancer of Split (Tle) family gene, Tle6-like. Expression of Tle6-like, or the similar human TLE6D splice isoform in colon cancer cells increased cell proliferation, colony-formation, cell migration, and xenograft tumorgenicity. Tle6-like;TLE6D directly interact with the gastrointestinal tumor suppressor RUNX3 and antagonize RUNX3 target transactivation. TLE6D is recurrently overexpressed in human colorectal cancers and TLE6D expression correlates with RUNX3 expression. Collectively, these findings provide important insights into the molecular mechanisms of individual MutL homologue tumor suppression and demonstrate an association between TLE mediated antagonism of RUNX3 and accelerated human colorectal cancer progression.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pgen.1000092en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410297/pdf/en_US
dash.licenseLAA
dc.titleNovel Roles for MLH3 Deficiency and TLE6-Like Amplification in DNA Mismatch Repair-Deficient Gastrointestinal Tumorigenesis and Progressionen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorKucherlapati, Raju
dc.date.available2013-01-29T16:44:52Z
dash.affiliation.otherHMS^Medicine-Brigham and Women's Hospitalen_US
dash.affiliation.otherHMS^Geneticsen_US
dc.identifier.doi10.1371/journal.pgen.1000092*
dash.contributor.affiliatedChen, Peng-Chieh
dash.contributor.affiliatedEdwards, Robert
dash.contributor.affiliatedKucherlapati, Raju


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