DNA damage-dependent translocation of B23 and p19 ARF is regulated by the Jun N-terminal kinase pathway.
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-NH(2)-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 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.
Yogev
Orli
O
Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel.
Saadon
Keren
K
Anzi
Shira
S
Inoue
Kazushi
K
Shaulian
Eitan
E
D002466:Cell Nucleolus / Q000378:metabolism*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010766:Phosphorylation; D021381:Protein Transport; D013912:Threonine / Q000378:metabolism; D014466:Ultraviolet Rays
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D013912:Threonine; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4