TY - JOUR
T1 - An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation
AU - López-Contreras, Andres J
AU - Gutierrez-Martinez, Paula
AU - Specks, Julia
AU - Rodrigo-Perez, Sara
AU - Fernandez-Capetillo, Oscar
PY - 2012/3/12
Y1 - 2012/3/12
N2 - Replicative stress (RS) is a type of endogenous DNA damage that cells suffer every time they duplicate their genomes, and which is further boosted by oncogenes. In mammals, the RS response (RSR) is coordinated by ATR and Chk1 kinases. We sought to develop a mammalian organism that is selectively protected from RS. To this end, mice carrying an extra copy of the Chk1 gene were generated. In vitro, Chk1 transgenic cells are protected from RS-inducing agents. Moreover, an extra Chk1 allele prolongs the survival of ATR-Seckel mice, which suffer from high levels of RS, but not that of ATM-deficient mice, which accumulate DNA breaks. Surprisingly, increased Chk1 levels favor transformation, which we show is associated with a reduction in the levels of RS induced by oncogenes. Our study provides the first example where supra-physiological levels of a tumor suppressor can promote malignant transformation, which is a result of the protection from the RS found in cancer cells.
AB - Replicative stress (RS) is a type of endogenous DNA damage that cells suffer every time they duplicate their genomes, and which is further boosted by oncogenes. In mammals, the RS response (RSR) is coordinated by ATR and Chk1 kinases. We sought to develop a mammalian organism that is selectively protected from RS. To this end, mice carrying an extra copy of the Chk1 gene were generated. In vitro, Chk1 transgenic cells are protected from RS-inducing agents. Moreover, an extra Chk1 allele prolongs the survival of ATR-Seckel mice, which suffer from high levels of RS, but not that of ATM-deficient mice, which accumulate DNA breaks. Surprisingly, increased Chk1 levels favor transformation, which we show is associated with a reduction in the levels of RS induced by oncogenes. Our study provides the first example where supra-physiological levels of a tumor suppressor can promote malignant transformation, which is a result of the protection from the RS found in cancer cells.
KW - Alleles
KW - Animals
KW - Ataxia Telangiectasia Mutated Proteins
KW - Cell Cycle Proteins
KW - Cell Transformation, Neoplastic
KW - DNA Damage
KW - DNA-Binding Proteins
KW - Dwarfism
KW - Gene Dosage
KW - Mice
KW - Mice, Knockout
KW - Mice, Mutant Strains
KW - Mice, Transgenic
KW - Microcephaly
KW - Oncogenes
KW - Protein Kinases
KW - Protein-Serine-Threonine Kinases
KW - Tumor Suppressor Proteins
U2 - 10.1084/jem.20112147
DO - 10.1084/jem.20112147
M3 - Journal article
C2 - 22370720
SN - 0022-1007
VL - 209
SP - 455
EP - 461
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 3
ER -
