DJ-1 Enhances Cell Survival through the Binding of Cezanne, a Negative Regulator of NF-κB

• Published in: The Journal of biological chemistry 2011-02, Vol.286 (6), p.4098-4106
• Main Authors: McNally, R. Sean, Davis, Beckley K., Clements, Casey M., Accavitti-Loper, Mary Ann, Mak, Tak W., Ting, Jenny P.-Y.
• Format: Article
• Language: English
• Subjects: Cancer Tumor Promoter; Cell Biology; Cezanne; Deubiquitination; DJ-1; ICAM-1; Interleukin; NF-kappa B; Parkinson's Disease
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.147371

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.