Haploinsufficiency of Krüppel-like factor 5 rescues the tumor-initiating effect of the Apc(Min) mutation in the intestine.
Inactivation of the tumor suppressor adenomatous polyposis coli, with the resultant activation of beta-catenin, is the initiating event in the development of a majority of colorectal cancers. Krüppel-like factor 5 (KLF5), a proproliferative transcription factor, is highly expressed in the proliferating intestinal crypt epithelial cells. To determine whether KLF5 contributes to intestinal adenoma formation, we examined tumor burdens in Apc(Min/+) mice and Apc(Min/+)/Klf5(+/-) mice. Compared with Apc(Min/+) mice, Apc(Min/+)/Klf5(+/-) mice had a 96% reduction in the number of intestinal adenomas. Reduced tumorigenicity in the Apc(Min/+)/Klf5(+/-) mice correlated with reduced levels and nuclear localization of beta-catenin as well as reduced expression of two beta-catenin targets, cyclin D1 and c-Myc. In vitro studies revealed a physical interaction between KLF5 and beta-catenin that enhanced the nuclear localization and transcriptional activity of beta-catenin. Thus, KLF5 is necessary for the tumor-initiating activity of beta-catenin during intestinal adenoma formation in Apc(Min/+) mice, and reduced expression of KLF5 offsets the tumor-initiating activity of the Apc(Min) mutation by reducing the nuclear localization and activity of beta-catenin.
Division of Digestive Diseases, Department of Medicine, Department of Pharmacology, and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Beth B
BB
McConnell
Agnieszka B
AB
Bialkowska
Mandayam O
MO
Nandan
Amr M
AM
Ghaleb
Frank J
FJ
Gordon
Vincent W
VW
Yang
D000236:Adenoma / Q000235:genetics / Q000517:prevention & control*; D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000473:pathology; D002522:Chlorocebus aethiops; D015179:Colorectal Neoplasms / Q000235:genetics*; D004254:DNA Nucleotidyltransferases / Q000235:genetics; D017491:Genes, APC; D006580:Genetic Carrier Screening; D006239:Haplotypes; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000517:prevention & control; D007422:Intestines / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C495267:CTNNB1 protein, mouse; C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051176:beta Catenin; D004254:DNA Nucleotidyltransferases; C062905:min recombinase