Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to 20S proteasomal degradation of p63 resulting in thinning of epithelium and chemical-induced skin cancer.
Disruption of NAD(P)H:quinone oxidoreductase 1 gene in mice leads to 20S proteasomal degradation of p63 resulting in thinning of epithelium and chemical-induced skin cancer.
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DOI：
10.1038/onc.2010.491
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发表时间：
2011-03-03
期刊：
影响因子：
8
通讯作者：
Jaiswal, A. K.
中科院分区：
文献类型：
--
作者：
Patrick, B. A.;Gong, X.;Jaiswal, A. K.
NAD（P）H：醌氧化还原酶1（NQO 1）是一种细胞溶质酶，可保护细胞免受化学和辐射诱导的氧化应激和皮肤癌。小鼠NQO 1基因的破坏显示皮肤上皮变薄和细胞角蛋白14（皮肤分化的早期标志物）的丢失。免疫组织化学和Western分析表明，与野生型（WT）小鼠相比，NQO 1 −/−小鼠皮肤中的p63下调。进一步的分析包括NQO 1表达的调节，揭示了皮肤源性角质形成细胞和真皮成纤维细胞中NQO 1和p63水平之间的直接相关性。蛋白酶体活性的调节揭示了p63被20 S蛋白酶体降解，并且这种降解被NQO 1显著拯救。免疫共沉淀研究表明，NQO 1直接与p63相互作用，但不与20 S相互作用，以防止这种降解。此外，苯并[a]芘处理导致WT中NQO 1的诱导和p63的稳定，但在NQO 1 −/−小鼠皮肤和角质形成细胞中没有。这些数据表明，NQO 1控制p63的稳定和角质形成细胞分化的进展，导致正常的皮肤发育和可能的皮肤癌变。
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic enzyme that protects cells against chemical and radiation-induced oxidative stress and skin cancer. Disruption of NQO1 gene in mice showed thinning of skin epithelium and loss of cytokeratin 14, an early marker of skin differentiation. Immunohistochemistry and western analysis demonstrated downregulation of p63 in NQO1−/− mouse skin, as compared with wild-type (WT) mouse. Further analysis including modulation of NQO1 expression revealed a direct correlation between the levels of NQO1 and p63 in skin-derived keratinocytes and dermal fibroblasts. Modulation of proteasomal activity revealed that p63 is degraded by 20S proteasome and that this degradation is significantly rescued by NQO1. Coimmunoprecipitation studies showed that NQO1 interacts directly with p63 but not 20S to protect against this degradation. In addition, benzo[a]pyrene treatment led to induction of NQO1 and stabilization of p63 inWT but not in NQO1−/− mouse skin and keratinocytes. These data suggest that NQO1 controls stabilization of p63 and progression towards keratinocyte differentiation leading to normal skin development and presumably skin carcinogenesis.
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影响因子：
7.4
作者：
Chen, S;Wu, KB;Knox, R
通讯作者：
Knox, R
影响因子：
3.7
作者：
Romano RA;Ortt K;Birkaya B;Smalley K;Sinha S
通讯作者：
Sinha S
影响因子：
8
作者：
Pietsch, E. C.;Sykes, S. M.;McMahon, S. B.;Murphy, M. E.
通讯作者：
Murphy, M. E.
影响因子：
64.8
作者：
Mills, AA;Zheng, BH;Bradley, A
通讯作者：
Bradley, A
DOI：
10.1073/pnas.91.18.8413
发表时间：
1994-08-30
影响因子：
11.1
作者：
JOSEPH, P;JAISWAL, AK
通讯作者：
JAISWAL, AK