title: Differential p53 engagement in response to oxidative and oncogenic stresses in Fanconi anemia mice.
abstract: 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.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: 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
chemical_list: C120277:Fanca protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide