title: DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB.
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.
authors.affiliation: Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
authors.forename: R Sean
authors.initials: RS
authors.lastname: McNally
authors.forename: Beckley K
authors.initials: BK
authors.lastname: Davis
authors.forename: Casey M
authors.initials: CM
authors.lastname: Clements
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Accavitti-Loper
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Jenny P-Y
authors.initials: JP
authors.lastname: Ting
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C464790:Bbs1 protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D015513:Oncogene Proteins; D011506:Proteins; D018799:Intercellular Adhesion Molecule-1; D054464:Peroxiredoxins; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D010450:Endopeptidases; C476458:OTUD7B protein, human