Mlh1 deficiency enhances several phenotypes of Apc(Min)/+ mice.
Defects in APC and DNA mismatch repair genes are associated with a strong predisposition to colon cancer in humans, and numerous mouse strains with mutations in these genes have been generated. In this report we describe the phenotype of Min/+ Mlh1-/- mice. We find that these doubly mutant mice develop more than three times the number of intestinal adenomas compared to Min/+ Mlh1+/+ or +/- mice but that these tumors do not show advanced progression in terms of tumor size or histological appearance. Full length Apc protein was not detected in the tumor cells from Min/+ Mlh1-/- mice. Molecular analyses indicated that in many tumors from Min/+ Mlh1-/- mice, Apc was inactivated by intragenic mutation. Mlh1 deficiency in Min/+ mice also led to an increase in cystic intestinal crypt multiplicity as well as enhancing desmoid tumorigenesis and epidermoid cyst development. Thus, Mlh1 deficiency influences the somatic events involved in the development of most of the phenotypes associated with the Min mutation. Oncogene (2000).
Shoemaker
A R
AR
McArdle Laboratory for Cancer Research and Laboratory of Genetics, University of Wisconsin Medical School, Madison, Wisconsin, WI 53706, USA.
Haigis
K M
KM
Baker
S M
SM
Dudley
S
S
Liskay
R M
RM
Dove
W F
WF
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics*; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D009687:Nuclear Proteins; D010641:Phenotype
D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C501485:Mlh1 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1