Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice.
Members of the Fanconi anemia (FA) protein family are involved in repair of genetic damage caused by DNA cross-linkers. It is not clear whether the FA proteins function in oxidative DNA damage and oncogenic stress response. Here, we report that deficiency in the Fanca gene in mice elicits a p53-dependent growth arrest and DNA damage response to oxidative DNA damage and oncogenic stress. Using a Fanca-/-Trp53-/- double knockout model and a functionally switchable p53 retrovirus, we define the kinetics, dependence, and persistence of p53-mediated response to oxidative and oncogenic stresses in Fanca-/- cells. Notably, oxidative stress induces persistent p53 response in Fanca-/- cells, likely due to accumulation of unrepaired DNA damage. On the other hand, whereas wild-type cells exhibit prolonged response to oncogene activation, the p53-activating signals induced by oncogenic ras are short-lived in Fanca-/- cells, suggesting that Fanca may be required for the cell to engage p53 during constitutive ras activation. We propose that the FA proteins protect cells from stress-induced proliferative arrest and tumor evolution by acting as a modulator of the signaling pathways that link FA to p53.
Rani
Reena
R
Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Li
Jie
J
Pang
Qishen
Q
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide