Nuclear factor-kappaB protects the liver against genotoxic stress and functions independently of p53.
p53 and NF-kappaB are two key effectors in the chemotherapy-induced genotoxic response. Although p53 is a universal inducer of apoptotosis in many stress responses, including the genotoxic response, the role of nuclear factor (NF)-kappaB is not consistent and was reported to both counteract and mediate apoptosis. Although the reason for the apparent contradictory effects of NF-kappaB is not understood, it may partly be related to the reported cross-regulation of NF-kappaB and p53. Thus far, all studies exploring the cross-talk between p53 and NF-kappaB in conjunction with apoptosis have been performed in tissue-cultured cells and may therefore not faithfully represent conditions that prevail within a chemotherapy-subjected organism. To address this concern, we examined the respective roles of NF-kappaB and p53 in a liver model of doxorubicin-induced DNA damage. Using this animal model, we report that NF-kappaB is activated in response to doxorubicin-induced genotoxic stress and exerts a pronounced protective effect in opposing chemotherapy-induced tissue damage. Importantly, the activation of NF-kappaB occurs independently of p53 status. Furthermore, although p53 is also induced in this in vivo system, its induction is independent of NF-kappaB and does not contribute to the extent of tissue damage. These findings may have important implications with respect to the potential use of NF-kappaB modulators in cancer therapy.
Lavon
Iris
I
The Lautenberg Center for Immunology, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Pikarsky
Eli
E
Gutkovich
Elena
E
Goldberg
Iris
I
Bar
Jair
J
Oren
Moshe
M
Ben-Neriah
Yinon
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004249:DNA Damage; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009153:Mutagens / Q000633:toxicity*; D016328:NF-kappa B / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D009153:Mutagens; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin