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DNA Damage–Dependent Translocation of B23 and p19^ARF Is Regulated by the Jun N-Terminal Kinase Pathway

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 • p19^ARF • 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, p14^ARF/p19^ARF 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 p19^ARF 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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