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Stress-induced NQO1 controls stability of C/EBP? against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

ABSTRACT: Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBP?) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of the NQO1 gene in mice and mouse keratinocytes led to degradation of C/EBP? and loss of p63 gene expression. p63 promoter mutagenesis, transfection and chromatin immunoprecipitation assays identified a C/EBP?-binding site between nucleotide position -185 and -174 that bound to C/EBP? and upregulated p63 gene expression. Co-immunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBP?. NQO1 direct interaction with C/EBP? led to stabilization of C/EBP? against 20S proteasomal degradation. NQO1 protection of C/EBP? required binding of NADH with NQO1. Exposure of skin and keratinocytes to the chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBP? protein, resulting in an increase in p63 RNA and protein in wild-type but not in NQO1-/- mice. Collectively, the current data combined with previous data suggest that stress induction of NQO1 through both stabilization of C/EBP? and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation, leading to protection against chemical-induced skin carcinogenesis. The studies are significant as 2-4% human individuals are homozygous and 23% are heterozygous for the NQO1P187S mutation and might be susceptible to stress-induced skin diseases.

SUBMITTER: Patrick BA

PROVIDER: S-EPMC3538879 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Patrick B A BA Jaiswal A K AK

Oncogene 20120116 40

Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in the stabilization of p63 against 20S proteasomal degradation resulting in thinning of the epithelium and chemical-induced skin cancer (Oncogene (2011) 30, 1098-1107). Current studies have demonstrated that NQO1 control of CCAAT-enhancer binding protein (C/EBPα) against 20S proteasomal degradation also contributes to the upregulation of p63 expression and protection. Western and immunohistochemistry analysis ...[more]

PMID: 22249251

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Project description:The current study evaluates the cytotoxicity, mode of cell death and chemical analysis of selected beauty products and evaluation of the protective effect of Tamarix articulata (TA) extract against toxicity induced by beauty products in skin fibroblasts (Hs27). MTT and Crystal violet (CV) assays were used to determine the dose-dependent cytotoxic effects of beauty products against Hs27 fibroblasts. DNA fragmentation assay and annexin-V staining were conducted to determine the mode of cell killing induced by evaluated beauty products. Quantification of reactive oxygen species (ROS) and antioxidant enzyme levels were used to evaluate the oxidative stress. Chemical analysis and heavy metals were evaluated to determine beauty products. Pre-treatment with TA extract for different time points followed by time-dependent exposure with beauty products to assess the protective effect of TA extract in Hs27 cells was analyzed by MTT and CV assays. Owing to the presence of various harmful heavy metals such as arsenic (As), chromium (Cr), cadmium (Cd), nickel (Ni), and lead (Pb) in beauty products, our results revealed that all beauty products induce significant cytotoxicity over time (1, 4 h) in a dose-dependent (125, 250, 500 μg/mL) manner. DNA fragmentation assay, quantification of apoptosis by annexin-V staining, determination of ROS and antioxidant enzymes (CAT, GSH-Px and SOD) revealed that the induced cytotoxicity was caused by oxidative stress-mediated apoptosis. However, pre-incubation with a safe dose (50 μg/mL) of TA for different times (24, 48 h) followed by exposure to various doses (62.5, 125, 250, 500 μg/mL) of beauty products for different times (1, 4 h) revealed significant (*p≤0.05, **p≤0.01) protection against beauty product-mediated cytotoxicity. The effect was more pronounced for 1 h exposure to beauty products compared to 4 h. Our study demonstrates that the due to the presence of heavy metals in synthetic beauty products exhibit marked toxicity to skin fibroblasts due to oxidative stress-mediated apoptosis. However, the presence of abundant bioactive polyphenols with promising antiscavenging activity in TA extracts significantly nullifies cytotoxicity promoted by examined beauty products in skin fibroblasts (Hs27).

Dataset Information

Stress-induced NQO1 controls stability of C/EBP? against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Publications

Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer.

Similar Datasets

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