oxidative stress ͉ PARK7 ͉ NQO1 ͉ Keap1 ͉ neurodegeneration

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-B 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-B 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-B 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.Lung cancer is the leading cause of cancer-related mortality in the world. It is estimated that over 215,000 new cases were diagnosed in the United States in 2008 alone (1). Of the two major types of lung cancer, 85% are non-small cell lung carcinomas (NSCLC) 2 (2). With NSCLC, the best chance for a long term cure is surgery. Unfortunately, 70% of NSCLC patients are initially contraindicated for surgery due to locally invasive or metastatic disease (3). For these patients, the current treatment options are a combination of chemotherapy and radiation. With treatment, NSCLC patients have a 5-year survival rate of 15%. It is therefore imperative to investigate new pathways to target in NSCLC. Our work in the H157 NSCLC squamous cell line has focused on the role of DJ-1.DJ-1 is associated with a spectrum of human disease. Loss of DJ-1 activity, due to inactivation by mutation or genetic deletion, causes early onset Parkinson disease with high penetrance (4). Due to the protective effects of DJ-1 against toxic insults, this association is hypothesized to be due to a protective role of DJ-1 in dopaminergic neurons of the substantia nigra (5-7). As loss of DJ-1 activity leads to neuronal cell death, increased DJ-1 activity can promote cell survival, leading to its association with human malignancies. Initial research on the role of DJ-1 in cancer showed that although DJ-1 can weakly transform cells alone, it can act synergistically in combination with Ras (8). DJ-1 is highly expressed in a number of cancer types including acute leukemia, breast, prostate, ovarian, and thyroid cancer, and NSCLC and is associated with tumo...

Macrophage inflammatory protein 1α (MIP-1α), a CC chemokine, is a chemoattractant for T cells and immature dendritic cells. Plasmacytoma cells expressing MIP-1α generate a cytotoxic T cell response without affecting tumor growth. To understand this discrepancy, we compared a local tumor model with a metastatic one using MIP-1α-transfected B16 F10 melanoma cells. Clonal idiosyncrasies were controlled by selecting three lipotransfected tumor clones and two pcDNA vector transfected control clones with equivalent in vitro proliferative capacities. No significant differences were seen between the MIP-1α-producing and control melanoma cells after s.c. injection in the hind leg. All animals had a leg diameter of 10 cm in 18.5–21.5 days. However, after i.v. injection the number of pulmonary foci was significantly reduced in the MIP-1α-producing clones. Injection of 106 control transfected cells resulted in a median of 98.5 tumor foci in 2 wk, whereas the injection of the MIP-1α-producing clones resulted in 89.5, 26.5, and 0 foci. The number of metastatic foci was inversely proportional to the amount of MIP-1α produced by the clone in vitro. Flow cytometry showed a significant increase in CD8+ cells in lungs of mice with MIP-1α-transfected tumors 3 days after injection. This increase was not maintained 10 days later despite continued production of MIP-1α. The protection offered by transfection with MIP-1α was significantly impaired in β2-microglobulin−/− mice. Our findings suggest that MIP-1α is effective in preventing the initiation of metastasis, but not at sustaining an effective antitumor response.

RTLS doubled the potential pertussis exposures beyond EMR-based contact identification. Thus, RTLS may be a valuable addition to the practice of contact tracing and infectious disease monitoring.

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