Novel roles for MLH3 deficiency and TLE6-like amplification in DNA mismatch repair-deficient gastrointestinal tumorigenesis and progression. Academic Article uri icon

Overview

MeSH

  • Adenomatous Polyposis Coli Protein
  • Adenosine Triphosphatases
  • Alternative Splicing
  • Animals
  • Base Sequence
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Core Binding Factor Alpha 3 Subunit
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Disease Progression
  • Female
  • Gene Dosage
  • Humans
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Nude
  • Mice, Transgenic
  • Mismatch Repair Endonuclease PMS2
  • MutL Proteins
  • Mutation
  • Neoplasm Transplantation
  • Protein Isoforms
  • Transcriptional Activation
  • Transplantation, Heterologous

MeSH Major

  • Carrier Proteins
  • Colorectal Neoplasms
  • DNA Mismatch Repair
  • Gene Amplification
  • Repressor Proteins
  • Transcription Factors

abstract

  • 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.

publication date

  • June 13, 2008

has subject area

  • Adenomatous Polyposis Coli Protein
  • Adenosine Triphosphatases
  • Alternative Splicing
  • Animals
  • Base Sequence
  • Carrier Proteins
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms
  • Core Binding Factor Alpha 3 Subunit
  • DNA Mismatch Repair
  • DNA Repair Enzymes
  • DNA-Binding Proteins
  • Disease Progression
  • Female
  • Gene Amplification
  • Gene Dosage
  • Humans
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Nude
  • Mice, Transgenic
  • Mismatch Repair Endonuclease PMS2
  • MutL Proteins
  • Mutation
  • Neoplasm Transplantation
  • Protein Isoforms
  • Repressor Proteins
  • Transcription Factors
  • Transcriptional Activation
  • Transplantation, Heterologous

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2410297

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1000092

PubMed ID

  • 18551179

Additional Document Info

start page

  • e1000092

volume

  • 4

number

  • 6