Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun.
The transformation suppressor gene Pdcd4 (programmed cell death gene 4) inhibits the tumor-promoter mediated transformation of mouse keratinocytes and has recently been implicated as a potential tumor suppressor gene in the development of human lung cancer. Biochemical analysis has suggested that the Pdcd4 protein is involved in protein translation as well as in nuclear events. Recent work has shown that Pdcd4 suppresses the transactivation of AP-1 responsive promoters by c-Jun, suggesting that the transformation-suppressor activity of Pdcd4 might be due, at least in part, to the inhibition of c-Jun activity. Here, we have addressed how Pdcd4 inhibits c-Jun. We show that Pdcd4 interferes with the phosphorylation of c-Jun by Jun N-terminal kinase (JNK). The inhibition of c-Jun phosphorylation by Pdcd4 appears not to be due to a general suppression of JNK activity, our data rather suggest that Pdcd4 interacts with c-Jun and thereby blocks phosphorylation of c-Jun. In addition to affecting c-Jun phosphorylation, Pdcd4 blocks the recruitment of the coactivator p300 by c-Jun. Taken together, our results strongly suggest that Pdcd4 is directly involved in the regulation of c-Jun activity.
Bitomsky
Nadja
N
Institut für Biochemie, Westfälische-Wilhelms-Universität Münster, Wilhelm-Klemm-Str. 2, D-48149, Germany.
Böhm
Maret
M
Klempnauer
Karl-Heinz
KH
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011784:Quail; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D009687:Nuclear Proteins; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases