Chk1 deficiency in the mouse small intestine results in p53-independent crypt death and subsequent intestinal compensation.
Chk1 is a serine/threonine protein kinase that is activated by a wide range of DNA-damaging agents to slow the cell cycle during S phase and G2/M. Abrogation of these cell-cycle checkpoints using Chk1 inhibitors results in hypersensitivity to DNA-damaging agents in vitro and may provide a potential therapeutic tool to sensitize tumour cells in vivo. We have generated a Cre-Lox-based mouse model in which Chkl can be inducibly deleted from somatic epithelial cells in the adult mouse small intestine and liver. Loss of Chk1 in the liver is tolerated with no apparent phenotype. In contrast, the loss of Chk1 within the small intestine results in immediate DNA damage and high levels of p53-independent apoptosis leading to crypt death. However, the intestine is able to compensate for this death by undergoing complete re-population with Chk1-proficient cells. These data therefore show that Chk1 deficiency is cell lethal, but the intestine can tolerate such lethality at the organ level.
Greenow
K R
KR
Cardiff School of Biosciences, Cardiff University, Cardiff, UK.
Clarke
A R
AR
Jones
R H
RH
D000818:Animals; D017209:Apoptosis; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004249:DNA Damage; D006657:Histones / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D010766:Phosphorylation; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology*; D019324:beta-Naphthoflavone / Q000633:toxicity
D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D011494:Protein Kinases; D016159:Tumor Suppressor Protein p53; D019324:beta-Naphthoflavone; C000605869:Chek1 protein, mouse; C475961:gamma-H2AX protein, mouse