title: Wnt-driven intestinal tumourigenesis is suppressed by Chk1 deficiency but enhanced by conditional haploinsufficiency.
abstract: Chk1 is essential in maintaining genomic stability due to its role in cell cycle regulation. Several recent studies have indicated that the abrogation of checkpoints in tumourigenesis through the inhibition of Chk1 may be of therapeutic value. To further investigate the role of Chk1 in the mouse small intestine and its potential role as a therapy for colorectal cancer, we simultaneously deleted Chk1 and Apc in the mouse small intestine. We found that homozygous loss of Chk1 is not compatible with Wnt-driven proliferation and resulted in the suppression of Wnt-driven tumourigenesis in the mouse small intestine. In contrast, heterozygous loss of Chk1 in a Wnt-driven background resulted in an increase in DNA damage and apoptosis and accelerated both tumour development and progression.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: K R
authors.initials: KR
authors.lastname: Greenow
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: G T
authors.initials: GT
authors.lastname: Williams
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
authors.forename: R
authors.initials: R
authors.lastname: Jones
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D018450:Disease Progression; D057895:Haploinsufficiency; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse