Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc.
Programmed cell death 4 (Pdcd4) is a novel tumor suppressor, whose expression is frequently down-regulated in several types of cancers. In the present study, we demonstrated that Pdcd4 knockdown up-regulates MAP kinase kinase kinase kinase 1 (MAP4K1) expression and increases phosphorylation of c-Jun. Over-expression of c-Myc in HEK293 cells increases the levels of MAP4K1, MAP4K1 promoter activity, and phospho-c-Jun. Mutation analysis showed that the c-Myc binding site at -536bp (relative to the initiation ATG) of map4k1 promoter responds to c-Myc regulation. In addition, chromatin immunoprecipitation demonstrated that c-Myc directly binds to map4k1 promoter at this site. Down-regulation of c-Myc reverses MAP4K1 expression and AP-1 activation in Pdcd4 knockdown cells. Moreover, over-expression of dominant negative Tcf4 decreases expression of c-Myc and MAP4K1, JNK activation, and AP-1 dependent transcription. Thus, activation of β-catenin/Tcf dependent transcription in Pdcd4 knockdown cells up-regulates MAP4K1 expression and AP-1 activity via c-Myc. The study presented here further reveals in detail the mechanism of how Pdcd4 inhibits tumor cell invasion and provides a functional connection between β-catenin/Tcf and AP-1 dependent transcription.
Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Qing
Q
Wang
Yan
Y
Zhang
Hsin-Sheng
HS
Yang
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001665:Binding Sites; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C114487:PDCD4 protein, human; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D051820:TCF Transcription Factors; D018808:Transcription Factor AP-1; D051176:beta Catenin; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases