Selective inhibition of mitochondrial JNK signaling achieved using peptide mimicry of the sab kinase interacting motif-1 (KIM1)

Jeremy W. Chambers, Lisa Cherry, John D. Laughlin, Mariana Figuera-Losada, Philip V. Lograsso

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The c-jun N-terminal kinases (JNKs) are responsive to stress stimuli leading to activation of proapoptotic proteins and transcription. Additionally, JNK mitochondrial localization has been reported. To selectively target mitochondrial JNK signaling, we exploited JNK interaction with its mitochondrial scaffold, Sab, using small interfering RNAs (siRNAs) and a cell-permeable peptide corresponding to the KIM1 domain of Sab. Gene silencing and peptide interference of this interaction disrupted JNK translocation to the mitochondria and reduced phosphorylation of Bcl-2 without significant impact on c-Jun phosphorylation or AP-1 transcription. In contrast, the JNK inhibitory peptide (TI-JIP1) prevented these three functions. Tat-Sab KIM1 selectivity was also demonstrated in anisomycin-stressed HeLa cells where Tat-Sab KIM1 prevented Bcl-2 phosphorylation, cell death, loss of mitochondrial membrane potential, and superoxide generation but not c-Jun phosphorylation. Conversely, TI-JIP1 prevented all aforementioned stress-induced events. This probe introduces a means to evaluate JNK-mediated events on the mitochondria without intervening in nuclear functions of JNK.

Original languageEnglish (US)
Pages (from-to)808-818
Number of pages11
JournalACS Chemical Biology
Volume6
Issue number8
DOIs
StatePublished - Aug 19 2011
Externally publishedYes

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JNK Mitogen-Activated Protein Kinases
Phosphotransferases
Peptides
Phosphorylation
Mitochondria
Transcription
Anisomycin
Mitochondrial Membrane Potential
Transcription Factor AP-1
Gene Silencing
Cell death
HeLa Cells
Scaffolds
Superoxides
Small Interfering RNA
Cell Death
Genes
Chemical activation
Membranes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Selective inhibition of mitochondrial JNK signaling achieved using peptide mimicry of the sab kinase interacting motif-1 (KIM1). / Chambers, Jeremy W.; Cherry, Lisa; Laughlin, John D.; Figuera-Losada, Mariana; Lograsso, Philip V.

In: ACS Chemical Biology, Vol. 6, No. 8, 19.08.2011, p. 808-818.

Research output: Contribution to journalArticle

Chambers, Jeremy W. ; Cherry, Lisa ; Laughlin, John D. ; Figuera-Losada, Mariana ; Lograsso, Philip V. / Selective inhibition of mitochondrial JNK signaling achieved using peptide mimicry of the sab kinase interacting motif-1 (KIM1). In: ACS Chemical Biology. 2011 ; Vol. 6, No. 8. pp. 808-818.
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