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

Qing Wang, Yan Zhang, Hsin Sheng Yang

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Programme. d 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 -536 bp (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.

Original languageEnglish
Pages (from-to)1807-1814
Number of pages8
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Issue number10
StatePublished - Oct 2012

Bibliographical note

Funding Information:
This study was supported by a National Institute of Health grant ( RO1CA 129015 ).


  • AP-1
  • C-Myc
  • JNK signaling pathway
  • MAP4K1
  • Pdcd4

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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