TY - JOUR
T1 - c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function
T2 - A mechanism for oncogene-induced genetic instability
AU - Vafa, Omid
AU - Wade, Mark
AU - Kern, Suzanne
AU - Beeche, Michelle
AU - Pandita, Tej K.
AU - Hampton, Garret M.
AU - Wahl, Geoffrey M.
PY - 2002
Y1 - 2002
N2 - Oncogene overexpression activates p53 by a mechanism posited to involve uncharacterized hyperproliferative signals. We determined whether such signals produce metabolic perturbations that generate DNA damage, a known p53 inducer. Biochemical, cytological, cell cycle, and global gene expression analyses revealed that brief c-Myc activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated c-Myc partially disabled the p53-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. We propose that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.
AB - Oncogene overexpression activates p53 by a mechanism posited to involve uncharacterized hyperproliferative signals. We determined whether such signals produce metabolic perturbations that generate DNA damage, a known p53 inducer. Biochemical, cytological, cell cycle, and global gene expression analyses revealed that brief c-Myc activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated c-Myc partially disabled the p53-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. We propose that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.
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U2 - 10.1016/S1097-2765(02)00520-8
DO - 10.1016/S1097-2765(02)00520-8
M3 - Article
C2 - 12049739
AN - SCOPUS:0036285034
VL - 9
SP - 1031
EP - 1044
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -