Journal
CANCER RESEARCH
Volume 68, Issue 5, Pages 1398-1406Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-2865
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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. Thr(91) and Thr(93) 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 I 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.
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