c-Jun regulates phosphoinositide-dependent kinase 1 transcription: Implication for Akt and protein kinase C activities melanoma tumorigenesis

Pablo Lopez-Bergami, Hyungsoo Kim, Antimone Dewing, James Goydos, Stuart Aaronson, Ze'ev Ronai

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Mutations in N-RAS and B-RAF, which commonly occur in melanomas, result in constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) signaling. Active ERK increases expression and activity of the c-Jun transcription factor, linking ERK and Jun N-terminal kinase (JNK) cascades. Here, we show that c-Jun regulates transcription of phosphoinositide-dependent kinase 1 (PDK1) with a concomitant impact on Akt and protein kinase C (PKC) activity and related substrates. Inhibition of c-Jun reduces PDK1 expression and attenuates Akt and PKC activity, which can be restored by exogenous PDK1. c-Jun regulation of PDK1 in melanoma contributes to growth rate and the ability to form tumors in mice. Correspondingly, increased levels of c-Jun in melanoma cell lines coincide with up-regulation of PDK1 and phosphorylation of PKC and Akt. The identification of c-Jun as a transcriptional regulator of PDK1 expression highlights key mechanisms underlying c-Jun oncogenic activity, and provides new insight into the nature of up-regulated Akt and PKC in melanoma.

Original languageEnglish (US)
Pages (from-to)903-913
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number2
DOIs
StatePublished - 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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