DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB

J Biol Chem. 2011 Feb 11;286(6):4098-106. doi: 10.1074/jbc.M110.147371. Epub 2010 Nov 19.

Abstract

Heightened DJ-1 (Park7) expression is associated with a reduction in chemotherapeutic-induced cell death and poor prognosis in several cancers, whereas the loss of DJ-1 function is found in a subgroup of Parkinson disease associated with neuronal death. This study describes a novel pathway by which DJ-1 modulates cell survival. Mass spectrometry shows that DJ-1 interacts with BBS1, CLCF1, MTREF, and Cezanne/OTUD7B/Za20d1. Among these, Cezanne is a known deubiquitination enzyme that inhibits NF-κB activity. DJ-1/Cezanne interaction is confirmed by co-immunoprecipitation of overexpressed and endogenous proteins, maps to the amino-terminal 70 residues of DJ-1, and leads to the inhibition of the deubiquitinating activity of Cezanne. Microarray profiling of shRNA-transduced cells shows that DJ-1 and Cezanne regulate IL-8 and ICAM-1 expression in opposing directions. Similarly, DJ-1 enhances NF-κB nuclear translocation and cell survival, whereas Cezanne reduces these outcomes. Analysis of mouse Park7(-/-) primary cells confirms the regulation of ICAM-1 by DJ-1 and Cezanne. As NF-κB is important in cellular survival and transformation, IL-8 functions as an angiogenic factor and pro-survival signal, and ICAM-1 has been implicated in tumor progression, invasion, and metastasis; these data provide an additional modality by which DJ-1 controls cell survival and possibly tumor progression via interaction with Cezanne.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Animals
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • Cell Survival / genetics
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation / genetics
  • HEK293 Cells
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Interleukin-8 / biosynthesis
  • Interleukin-8 / genetics
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Microtubule-Associated Proteins
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peroxiredoxins
  • Protein Deglycase DJ-1
  • Proteins / genetics
  • Proteins / metabolism
  • Ubiquitination*

Substances

  • Bbs1 protein, human
  • CXCL8 protein, human
  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Oncogene Proteins
  • Proteins
  • Intercellular Adhesion Molecule-1
  • Peroxiredoxins
  • PARK7 protein, human
  • PARK7 protein, mouse
  • Protein Deglycase DJ-1
  • Endopeptidases
  • OTUD7B protein, human