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

Abstract

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.

• Authors: Qing Wang, Yan Zhang, Hsin-Sheng Yang
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1823 Issue 10 Pg. 1807-14 (Oct 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22801218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• PDCD4 protein, human
• Proto-Oncogene Proteins c-jun
• Proto-Oncogene Proteins c-myc
• RNA-Binding Proteins
• TCF Transcription Factors
• Transcription Factor AP-1
• beta Catenin
• hematopoietic progenitor kinase 1
• Protein Serine-Threonine Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• Apoptosis Regulatory Proteins (metabolism)
• Binding Sites
• Down-Regulation (genetics)
• Enzyme Activation
• Gene Knockdown Techniques
• HEK293 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Signaling System
• Models, Biological
• 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, metabolism)
• Transcription, Genetic
• Up-Regulation (genetics)
• beta Catenin (metabolism)