Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc

• Published in: Biochimica et biophysica acta Vol. 1823; no. 10; pp. 1807 - 1814
• Main Authors: Wang, Qing, Zhang, Yan, Yang, Hsin-Sheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2012
• Subjects: AP-1; Apoptosis Regulatory Proteins - metabolism; beta Catenin - metabolism; Binding Sites; c-Myc; Down-Regulation - genetics; Enzyme Activation; Gene Knockdown Techniques; HEK293 Cells; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; JNK signaling pathway; MAP Kinase Signaling System; MAP4K1; Models, Biological; Pdcd4; Promoter Regions, Genetic - genetics; Protein-Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins c-jun - metabolism; Proto-Oncogene Proteins c-myc - genetics; RNA-Binding Proteins - metabolism; TCF Transcription Factors - metabolism; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription, Genetic; Up-Regulation - genetics; MAP4K1; MKK4; TPA; c-Myc; JNK; DMBA; Pdcd4; siRNA; ChIP; AP-1; JNK signaling pathway; TAK1; ERK
• DOI: 10.1016/j.bbamcr.2012.07.004
• ISSN: 0167-4889; 0006-3002

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. [Display omitted] ► The c-Myc binds to MAP4K1 promoter and regulates MAP4K1 promoter activity. ► Down-regulation of c-Myc inhibits MAP4K1 expression and AP-1 activation. ► The dnTcf4 inhibits c-Myc and MAP4K1 expression. ► Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 via c-Myc.