Chk1 is haploinsufficient for multiple functions critical to tumor suppression.
The haploinsufficient tumor suppressor Chk1 is essential for embryonic cells, but the consequences of Chk1 loss in adult tissues are unknown. Using conditional Chk1 mice, we find that proliferating mammary cells lacking Chk1 undergo apoptosis leading to developmental defects. Conditional Chk1 heterozygosity increased the number of S phase cells and caused spontaneous DNA damage. Chk1+/- epithelia also exhibit a miscoordinated cell cycle in which S phase cells display an early mitotic phenotype. These cells maintain high levels of Cdc25A, which can promote inappropriate cell cycle transitions. Thus, Chk1 heterozygosity results in three distinct haploinsufficient phenotypes that can contribute to tumorigenesis: inappropriate S phase entry, accumulation of DNA damage during replication, and failure to restrain mitotic entry.
Lam
Michael H
MH
Baylor College of Medicine, Department of Molecular and Cellular Biology, Interdepartmental Program in Cellular and Molecular Biology, Houston, Texas 77030, USA.
Liu
Qinghua
Q
Elledge
Stephen J
SJ
Rosen
Jeffrey M
JM
D000818:Animals; D017209:Apoptosis; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004261:DNA Replication; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D016147:Genes, Tumor Suppressor; D019426:Integrases; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008938:Mitosis; D009124:Muscle Proteins; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D016196:S Phase; D014764:Viral Proteins; D020687:cdc25 Phosphatases / Q000378:metabolism
D008840:Microfilament Proteins; D009124:Muscle Proteins; C058992:Tagln protein, mouse; D014764:Viral Proteins; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C045073:Cre recombinase; D019426:Integrases; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases