title: Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis.
abstract: Chk1 is a key regulator of DNA damage checkpoint responses and genome stability in eukaryotes. To better understand how checkpoint proficiency relates to cancer development, we investigated the effects of genetic ablation of Chk1 in the mouse skin on tumors induced by chemical carcinogens. We found that homozygous deletion of Chk1 immediately before carcinogen exposure strongly suppressed benign tumor (papilloma) formation, and that the few, small lesions that formed in the ablated skin always retained Chk1 expression. Remarkably, Chk1 deletion rapidly triggered spontaneous cell proliferation, γ-H2AX staining and apoptosis within the hair follicle, a principal site of origin for carcinogen-induced tumors. At later times, the ablated skin was progressively repopulated by non-recombined Chk1-expressing cells and ultimately normal sensitivity to tumor induction was restored when carcinogen treatment was delayed. In marked contrast, papillomas formed normally in Chk1 hemizygous skin but showed an increased propensity to progress to carcinoma. Thus, complete loss of Chk1 is incompatible with epithelial tumorigenesis, whereas partial loss of function (haploinsufficiency) fosters benign malignant tumor progression.
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow, UK.
authors.forename: L M
authors.initials: LM
authors.lastname: Tho
authors.forename: S
authors.initials: S
authors.lastname: Libertini
authors.forename: R
authors.initials: R
authors.lastname: Rampling
authors.forename: O
authors.initials: O
authors.lastname: Sansom
authors.forename: D A
authors.initials: DA
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D017209:Apoptosis; D002273:Carcinogens; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D018450:Disease Progression; D017353:Gene Deletion; D042822:Genomic Instability; D051379:Mice; D018345:Mice, Knockout; D010212:Papilloma / Q000139:chemically induced*; D011494:Protein Kinases / Q000235:genetics*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D002273:Carcinogens; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse