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Cancer Research 68, 1398-1406, March 1, 2008. doi: 10.1158/0008-5472.CAN-07-2865
© 2008 American Association for Cancer Research

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Cell, Tumor, and Stem Cell Biology

DNA Damage–Dependent Translocation of B23 and p19ARF Is Regulated by the Jun N-Terminal Kinase Pathway

Orli Yogev1, Keren Saadon1, Shira Anzi1, Kazushi Inoue2 and Eitan Shaulian1

1 Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel and 2 Departments of Pathology/Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Requests for reprints: Eitan Shaulian, Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Ein Karem, Jerusalem 91120, Israel. Phone: 972-2-6757617; Fax: 972-2-6414583; E-mail: eshaulian{at}md.huji.ac.il.

Key Words: JNK • B23 • p19ARF • redistribution • AP-1

The dynamic behavior of the nucleolus plays a role in the detection of and response to DNA damage of cells. Two nucleolar proteins, p14ARF/p19ARF and B23, were shown to translocate out of the nucleolus after exposure of cells to DNA-damaging agents. This translocation affects multiple cellular functions, such as DNA repair, proliferation, and survival. In this study, we identify a pathway and scrutinize the mechanisms leading to the translocation of these proteins after exposure of cells to DNA-damaging agents. We show that redistribution of B23 and p19ARF after the exposure to genotoxic stress occurs preferentially when the c-Jun-NH2-kinase (JNK) pathway is activated and is inhibited when the JNK pathway is impaired. The stress-induced translocation of alternative reading frame (ARF) is JNK dependent and mediated by two activator proteins, c-Jun and JunB. Thr91 and Thr93 of c-Jun are required for the translocation, but the transcriptional activity of c-Jun is dispensable. Instead, c-Jun interacts with B23 in a dose-dependent manner. c-Jun itself is excluded from the nucleolus in a JNK-dependent manner. Hence, we suggest that c-Jun translocates B23 and ARF from the nucleolus after JNK activation by means of protein interactions. In senescent cells, JNK activity and c-Jun levels are reduced concomitantly with ARF nucleolar accumulation, and UV radiation does not cause the translocation of ARF. [Cancer Res 2008;68(5):1398–406]







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Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2008 by the American Association for Cancer Research.