English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

DNA 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.

Novel Roles for MLH3 Deficiency and TLE6-Like Amplification in DNA Mismatch Repair-Deficient Gastrointestinal Tumorigenesis and Progression