Choice of Biological Source Material Supersedes Oxidative Stress in Its Influence on DJ-1 in Vivo Interactions with Hsp90

Knobbe, Christiane B.; Revett, Timothy J.; Bai, Yueyu; Chow, Vinca; Jeon, Amy Hye Won; Böhm, Christopher; Ehsani, Sepehr; Kislinger, Thomas; Mount, Howard T.J.; Mak, Tak W.; George-Hyslop, Peter St; Schmitt‐Ulms, Gerold

doi:10.1021/pr200225c

Cited by 23 publications

(18 citation statements)

References 77 publications

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“…It is interesting to speculate that the disulfide interaction of Prdx2 and DJ-1 observed in this study could impact on Nrf2-dependent signaling, for example perhaps by modulating oxidation of the regulatory thiols in kelch-like ECH-associated protein 1 (keap1). The interaction of DJ-1 with Prdx1 and -6 has also been previously observed (48), although this was not increased by H 2 O 2 treatment. A non-covalent association of DJ-1 and -6 would perhaps logically explain why it is able to form the heterodisulfide dimer, which is unlikely unless DJ-1 Cys-53 is very abundant and highly reactive.…”

Section: Discussionsupporting

confidence: 70%

Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2

Fernandez-Caggiano

Schröder

Cho

et al. 2016

Journal of Biological Chemistry

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The role and responses of the dimeric DJ-1 protein to cardiac oxidative stress is incompletely understood. H 2 O 2 induces a 50-kDa DJ-1 interprotein homodimer disulfide, known to form between Cys-53 on each subunit. A trimeric 75-kDa DJ-1 complex that mass spectrometry shows contained 2-Cys peroxiredoxin also formed and precedes the appearance of the disulfide dimer. These observations may represent peroxiredoxin sensing and transducing the oxidant signal to DJ-1. The dimeric disulfide DJ-1 complex was stabilized by auranofin, suggesting that thioredoxin recycles it in cells. Higher concentrations of H 2 O 2 concomitantly induce DJ-1 Cys-106 hyperoxidation (sulfination or sulfonation) in myocytes, perfused heart, or HEK cells. An oxidation-resistant C53A DJ-1 shows potentiated H 2 O 2 -induced Cys-106 hyperoxidation. DJ-1 also forms multiple disulfides with unknown target proteins during H 2 O 2 treatment, the formation of which is also potentiated in cells expressing the C53A mutant. This suggests that the intersubunit disulfide induces a conformational change that limits Cys-106 forming heterodisulfide protein complexes or from hyperoxidizing. High concentrations of H 2 O 2 also induce cell death, with DJ-1 Cys-106 sulfonation appearing causal in these events, as expression of C53A DJ-1 enhanced both Cys-106 sulfonation and cell death. Nonetheless, expression of the DJ-1 C106A mutant, which fully prevents hyperoxidation, also showed exacerbated cell death responses to H 2 O 2 . A rational explanation for these findings is that DJ-1 Cys-106 forms disulfides with target proteins to limit oxidantinduced cell death. However, when Cys-106 is hyperoxidized, formation of these potentially protective heterodimeric disulfide complexes is limited, and so cell death is exacerbated.

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Section: Discussionsupporting

confidence: 70%

Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2

Fernandez-Caggiano

Schröder

Cho

et al. 2016

Journal of Biological Chemistry

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“…(30,31) Though our data were not conducted by 2-D analysis or surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF-MS), we believe that the level of DJ-1 detected in nipple fluid could support, in part, a more accurate diagnosis of breast cancer in combination with other biomarkers such as gross cystic disease fluid protein (GCDFP)-15, a1-acid glycoprotein, basic fibroblast growth factor, and HER2. (32)(33)(34) In summary, our findings suggest that the level of DJ-1 protein in nipple fluid is a potentially useful marker for the detection of breast cancer, with sensitivity and specificity superior to those of other clinical parameters, including cytology.…”

Section: Discussionmentioning

confidence: 79%

High levels of DJ‐1 protein in nipple fluid of patients with breast cancer

et al. 2012

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As we have previously demonstrated that some breast cancer cell lines secrete DJ-1 protein, we examined here whether breast cancer cells secrete DJ-1 protein in vivo. To this end, the levels of DJ-1 protein present in 136 specimens of nipple fluid was examined by enzyme-linked immunosorbent assay (ELISA). The average concentration of DJ-1 protein detected in diluted samples from 47 patients with invasive ductal carcinoma (IDC) was 22.4 ng/mL, while it was 18.6 ng/mL in 26 patients with ductal carcinoma in situ (DCIS). In contrast, the average DJ-1 concentration in samples from 63 women with benign lesions was 2.7 ng/mL, demonstrating that higher DJ-1 protein levels were detected in nipple fluid in the presence of cancer cells than in the presence of benign lesions (P < 0.0001). When a cut-off level of 3.0 ng/mL was applied, the higher level of DJ-1 was shown to be of significant clinical value for predicting the presence of breast cancer (85.9% specificity, 75% sensitivity; P < 0.0001). Multivariate logistic analysis that included established factors such as nipple discharge cytology, ductoscopic cytology, and carcinoembryonic antigen level further showed that the level of DJ-1 protein alone is of significant value for predicting the presence of breast cancer. Immunohistochemistry and in situ hybridization also showed that the low expression of DJ-1 protein, despite high mRNA expression, was significantly correlated with high DJ-1 protein levels in the nipple fluid. These data indicate that breast cancer cells secrete DJ-1 protein in vivo, and that its level is a potential indicator of breast cancer in patients with nipple discharge. (Cancer Sci 2012; 103: 1172-1176 N ipple discharge is a common complaint among women that is classified as normal or abnormal depending on features such as laterality, cyclic variation, quantity, or color.(1-3)Although the majority of cases of nipple discharge are due to benign conditions such as intraductal papilloma, ductal ectasia, or plasma cell mastitis, approximately 10-20% of cases are attributable to malignant conditions such as ductal carcinoma in situ (DCIS), or the early clinical stages of invasive ductal and/or lobular carcinoma. (4,5) While it has been proposed that patients with nipple discharge should undergo biopsy or subareolar exploration based on the presence or absence of a palpable mass, less invasive, non-surgical methods can also be applied in these cases. (6,7) The cytological evaluation of nipple discharge obtained directly from the nipple is widely used for clinical examination. In previous investigations of asymptomatic women with nipple discharge, a definitive diagnosis of malignancy was not possible in approximately 70% of cases (8,9) ; however, cytology has been improved by new techniques such as "duct lavage" and "duct endoscopy" (ductoscopy).(10-12) These newer techniques are designed to examine the abnormal cells that travel from the ducts to the nipple. Moreover, biological markers such as carcinoembryonic antigen (CEA) or human epidermal growth fac...

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“…The reported DJ-1/PARK7 mutations include deletions (Bonifati et al, 2003, Ramsey and Giasson, 2010) and missense mutations encoding several DJ-1 variants (Abou-Sleiman et al, 2003);(Hering et al, 2004); (Ramsey and Giasson, 2010). These mutations are hypothesized to induce a loss of the entire protein or loss-of-function versions of the protein (Bonifati et al, 2003), possibly by interfering with its homodimerization (Tao and Tong, 2003) or by forming unstable higher order complexes (Macedo et al, 2003, Knobbe et al, 2011). Visual symptoms such as dimness, blurring, blunted shapes, double vision and difficulty reading are common features in PD patients (Bodis-Wollner, 2002).…”

Section: Introductionmentioning

confidence: 99%

Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice

Bonilha

Bell

Rayborn

et al. 2015

Experimental Eye Research

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DJ-1/PARK7 mutations or deletions cause autosomal recessive early onset Parkinson’s disease (PD). Thus, DJ-1 protein has been extensively studied in brain and neurons. PD patients display visual symptoms; however, the visual symptoms specifically attributed to PD patients carrying DJ-1/PARK7 mutations are not known. In this study, we analyzed the structure and physiology of retinas of 3- and 6-month-old DJ-1 knockout (KO) mice to determine how loss of function of DJ-1 specifically contributes to the phenotypes observed in PD patients. As compared to controls, the DJ-1 KO mice displayed an increase in the amplitude of the scotopic ERG b-wave and cone ERG, while the amplitude of a subset of the dc-ERG components were decreased. The main structural changes in the DJ-1 KO retinas were found in the outer plexiform layer (OPL), photoreceptors and retinal pigment epithelium (RPE), which were observed at 3 months and progressively increased at 6 months. RPE thinning and structural changes within the OPL were observed in the retinas in DJ-1 KO mice. DJ-1 KO retinas also exhibited disorganized outer segments, central decrease in red/green cone opsin staining, decreased labeling of ezrin, broader distribution of ribeye labeling, decreased tyrosine hydroxylase in dopaminergic neurons, and increased 7,8- dihydro-8-oxoguanine-labeled DNA oxidation. Accelerated outer retinal atrophy was observed in DJ-1 KO mice after selective oxidative damage induced by a single tail vein injection of NaIO3, exposing increased susceptibility to oxidative stress. Our data indicate that DJ-1-deficient retinas exhibit signs of morphological abnormalities and physiological dysfunction in association with increased oxidative stress. Degeneration of RPE cells in association with oxidative stress is a key hallmark of age-related macular degeneration (AMD). Therefore, in addition to detailing the visual defects that occur as a result of the absence of DJ-1, our data is also relevant to AMD pathogenesis.

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Choice of Biological Source Material Supersedes Oxidative Stress in Its Influence on DJ-1 in Vivo Interactions with Hsp90

Cited by 23 publications

References 77 publications

Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2

Oxidant-induced Interprotein Disulfide Formation in Cardiac Protein DJ-1 Occurs via an Interaction with Peroxiredoxin 2

High levels of DJ‐1 protein in nipple fluid of patients with breast cancer

Loss of DJ-1 elicits retinal abnormalities, visual dysfunction, and increased oxidative stress in mice

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