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Nuclear Factor-B and Manganese Superoxide Dismutase Mediate Adaptive Radioresistance in Low-Dose Irradiated Mouse Skin Epithelial Cells

¹ Division of Molecular Radiobiology, School of Health Sciences and ² Purdue Cancer Center, Purdue University, West Lafayette, Indiana and ³ Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa

Requests for reprints: Jian Jian Li, Division of Molecular Radiobiology, School of Health Sciences, Purdue University, Room 1279, Civil Engineering Building, 550 Stadium Mall Drive, West Lafayette, IN 47907. Phone: 765-496-6792; Fax: 765-496-1377; E-mail: jjli{at}purdue.edu.

Mechanisms governing inducible resistance to ionizing radiation in untransformed epithelial cells pre-exposed to low-dose ionizing radiation (LDIR; 10 cGy) are not well understood. The present study provides evidence that pre-exposure to 10 cGy X-rays increases clonogenic survival of mouse skin JB6P+ epithelial cells subsequently exposed to 2 Gy doses of -rays. To elucidate the molecular pathways of LDIR-induced adaptive radioresistance, the transcription factor nuclear factor-B (NF-B) and a group of NF-B–related proteins [i.e., p65, manganese superoxide dismutase (MnSOD), phosphorylated extracellular signal-regulated kinase, cyclin B1, and 14-3-3] were identified to be activated as early as 15 min after LDIR. Further analysis revealed that a substantial amount of both 14-3-3 and cyclin B1 accumulated in the cytoplasm at 4 to 8 h when cell survival was enhanced. The nuclear 14-3-3 and cyclin B1 were reduced and increased at 4 and 24 h, respectively, after LDIR. Using YFP-fusion gene expression vectors, interaction between 14-3-3 and cyclin B1 was visualized in living cells, and LDIR enhanced the nuclear translocation of the 14-3-3/cyclin B1 complex. Treatment of JB6P+ cells with the NF-B inhibitor IMD-0354 suppressed LDIR-induced expression of MnSOD, 14-3-3, and cyclin B1 and diminished the adaptive radioresistance. In addition, treatment with small interfering RNA against mouse MnSOD was shown to inhibit the development of LDIR-induced radioresistance. Together, these results show that NF-B, MnSOD, 14-3-3, and cyclin B1 contribute to LDIR-induced adaptive radioresistance in mouse skin epithelial cells. [Cancer Res 2007;67(7):3220–8]

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