title: c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK.
abstract: In order to activate gene expression, transcription factors such as c-Jun have to reside in the nucleus. The abundance of c-Jun in the nucleus correlates with the activity of its target genes. As a consequence of excessive c-Jun activation, cells undergo apoptosis or changes in differentiation whereas decreased c-Jun function can reduce proliferation. In the present study we addressed how nuclear accumulation of the transcription factor c-Jun is regulated. First, we analyzed which functions of c-Jun are required for efficient nuclear accumulation. Mutants of c-Jun deficient in dimerization or DNA-binding show no defect in nuclear transport. Furthermore, c-Jun import into the nucleus of living cells occurred when the c-Jun phosphorylation sites were mutated as well in cells that lack the major c-Jun kinase, JNK, suggesting that c-Jun transport into the nucleus does not require JNK signaling. Conversely, however, binding of c-Jun seemed to enhance nuclear accumulation of JNK. In order to identify proteins that might be relevant for the nuclear translocation of c-Jun we searched for novel binding partners by a proteomic approach. In addition to the heat shock protein HSP70 and the DNA damage repair factors Ku70 and 80, we isolated human importin 8 as a novel interactor of c-Jun. Interaction of Imp 8 with c-Jun in human cells was confirmed by co-immunoprecipitation experiments. Nuclear accumulation of c-Jun does not require its functions as a transcription factor or the interaction with its kinase JNK. Interestingly, nuclear accumulation of JNK is regulated by interaction with c-Jun. Unraveling the mechanisms of c-Jun and JNK transport to the nucleus and its regulation will improve our understanding of their role in biological and pathophysiological processes.
authors: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
authors: Ilona
authors: I
authors: Schreck
authors: Marco
authors: M
authors: Al-Rawi
authors: José-Manuel
authors: JM
authors: Mingot
authors: Christine
authors: C
authors: Scholl
authors: Markus Elmar
authors: ME
authors: Diefenbacher
authors: Paul
authors: P
authors: O'Donnell
authors: Dirk
authors: D
authors: Bohmann
authors: Carsten
authors: C
authors: Weiss
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000072200:Ku Autoantigen; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; C107282:IPO8 protein, human; D016755:Proto-Oncogene Proteins c-jun; D028961:beta Karyopherins; D048670:MAP Kinase Kinase 4; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen