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Nuclear Factor-B Protects the Liver against Genotoxic Stress and Functions Independently of p53¹

The Lautenberg Center for Immunology [I. L., E. G., Y. B-N.] and Department of Pathology [E. P.], The Hebrew University-Hadassah Medical School, Jerusalem 91120; Department of Pathology, Tel Aviv University Sackler Medical School and Sheba Medical Center, Tel-Hashomer 52621 [I. G.]; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100 [J. B., M. O.], Israel

p53 and NF-B 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)-B is not consistent and was reported to both counteract and mediate apoptosis. Although the reason for the apparent contradictory effects of NF-B is not understood, it may partly be related to the reported cross-regulation of NF-B and p53. Thus far, all studies exploring the cross-talk between p53 and NF-B 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-B and p53 in a liver model of doxorubicin-induced DNA damage. Using this animal model, we report that NF-B 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-B occurs independently of p53 status. Furthermore, although p53 is also induced in this in vivo system, its induction is independent of NF-B and does not contribute to the extent of tissue damage. These findings may have important implications with respect to the potential use of NF-B modulators in cancer therapy.

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