DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB.
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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Cell Nucleus, Cell Survival, Endopeptidases, Gene Expression Profiling, Gene Expression Regulation, HEK293 Cells, Humans, Intercellular Adhesion Molecule-1, Interleukin-8, Intracellular Signaling Peptides and Proteins, Mice, NF-kappa B, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Proteins, Ubiquitination
Active Transport, Cell Nucleus, Animals, Cell Nucleus, Cell Survival, Endopeptidases, Gene Expression Profiling, Gene Expression Regulation, HEK293 Cells, Humans, Intercellular Adhesion Molecule-1, Interleukin-8, Intracellular Signaling Peptides and Proteins, Mice, NF-kappa B, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasms, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Proteins, Ubiquitination
J. Biol. Chem.
Date: Feb. 11, 2011
PubMed ID: 21097510
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