ZBP-89-induced apoptosis is p53-independent and requires JNK

L. Bai, S. O. Yoon, P. D. King, J. L. Merchant

Research output: Contribution to journalReview articlepeer-review

43 Scopus citations

Abstract

ZBP-89 induces apoptosis in human gastrointestinal cancer cells through a p53-independent mechanism. To understand the apoptotic pathway regulated by ZBP-89, we identified downstream signal transduction targets. Ectopic expression of ZBP-89 induced apoptosis through the mitochondrial pathway and was accompanied by activation of all three MAP kinase subfamilies: JNK1/2, ERK1/2 and p38 MAP kinase. ZBP-89-induced apoptosis was markedly enhanced by ERK inhibition with U0126. In contrast, inhibiting JNK with a JNK1-specific peptide inhibitor or dominant-negative JNK2 expression abrogated ZBP-89-mediated apoptosis. The p38 inhibitor SB202190 had no effect on ZBP-89-induced cell death. Protein dephosphorylation assays revealed that ZBP-89 activates JNK via repression of JNK dephosphorylation. Oligonucleotide microarray analyses revealed that ectopic expression of ZBP-89 downregulated expression of the dual-specificity phosphatase MKP6. Overexpression of MKP6 blocked ZBP-89-induced JNK phosphorylation and PARP cleavage. In addition, ectopic expression of ZBP-89 repressed Bcl-xL and Mcl-1 expression, but had no effect on Bcl-2. Silencing ZBP-89 with small interfering RNA enhanced both Bcl-xL and Mcl-1 expression. Taken together, ZBP-89-mediated apoptosis occurs via a p53-independent mechanism that requires JNK activation.

Original languageEnglish (US)
Pages (from-to)663-673
Number of pages11
JournalCell Death and Differentiation
Volume11
Issue number6
DOIs
StatePublished - Jun 2004
Externally publishedYes

Keywords

  • Bcl-xL
  • Bid
  • Dephosphorylation
  • Mcl-1
  • siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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