Proteasome regulation of ULBP1 transcription.
Proteasome regulation of ULBP1 transcription.
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DOI：
10.4049/jimmunol.0801214
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发表时间：
2009-05-15
期刊：
影响因子：
--
通讯作者：
Lutz CT
中科院分区：
文献类型：
--
作者：
Butler JE;Moore MB;Presnell SR;Chan HW;Chalupny NJ;Lutz CT
杀伤淋巴细胞识别肿瘤上应激激活的NKG 2D配体。我们检测了头颈部鳞状细胞癌（HNSCC）细胞和其他细胞系中NKG 2D配体的表达。HNSCC细胞通常表达MHC I类链相关基因A（云母）、MICB、UL 16结合蛋白（ULBP）2和ULBP 3，但它们对细胞表面ULBP 1和ULBP 4均呈阴性。然后，我们研究了癌症治疗如何影响NKG 2D配体表达。大多数癌症相关治疗均未改变NKG 2D配体表达。然而，硼替佐米和其他具有不同作用机制的蛋白酶体抑制剂药物显著且特异性地上调HNSCC ULBP 1 mRNA和细胞表面蛋白。蛋白酶体抑制也增加了非转化人角质形成细胞中ULBP 1和其他NKG 2D配体的RNA。蛋白酶体抑制剂药物通过作用于522-bp ULBP 1启动子中的一个位点来增加ULBP 1的转录。虽然ATM（共济失调-毛细血管扩张症，突变）和ATR（ATM和Rad 3相关）信号介导的DNA损伤反应途径已被报道上调NKG 2D配体表达，我们发现，ULBP 1上调不受咖啡因和渥曼青霉素，ATM/ATR信号抑制剂。几种ATM/ATR活化处理，包括博来霉素、顺铂、阿非迪霉素和羟基脲，均未增加HNSCC细胞中ULBP 1的表达。电离辐射引起ATM激活HNSCC细胞，但高水平的ULBP 1表达不诱导γ辐射或紫外线辐射。因此，ATM/ATR信号既不是必需的，也不足以在人HNSCC细胞系中高水平表达ULBP 1，不能解释蛋白酶体效应。蛋白酶体抑制剂药物对ULBP 1表达的选择性诱导以及人肿瘤细胞对可变NKG 2D配体表达的沿着，表明NKG 2D配体基因受到独立调控。
Killer lymphocytes recognize stress-activated NKG2D ligands on tumors. We examined NKG2D ligand expression in head and neck squamous cell carcinoma (HNSCC) cells and other cell lines. HNSCC cells typically expressed MHC class I chain-related gene A (MICA), MICB, UL16-binding protein (ULBP)2, and ULBP3, but they were uniformly negative for cell surface ULBP1 and ULBP4. We then studied how cancer treatments affected NKG2D ligand expression. NKG2D ligand expression was not changed by most cancer-relevant treatments. However, bortezomib and other proteasome inhibitor drugs with distinct mechanisms of action dramatically and specifically up-regulated HNSCC ULBP1 mRNA and cell surface protein. Proteasome inhibition also increased RNA for ULBP1 and other NKG2D ligands in nontransformed human keratinocytes. Proteasome inhibitor drugs increased ULBP1 transcription by acting at a site in the 522-bp ULBP1 promoter. Although the DNA damage response pathways mediated by ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) signaling had been reported to up-regulate NKG2D ligand expression, we found that ULBP1 up-regulation was not inhibited by caffeine and wortmannin, inhibitors of ATM/ATR signaling. ULBP1 expression in HNSCC cells was not increased by several ATM/ATR activating treatments, including bleomycin, cisplatin, aphidicolin, and hydroxyurea. Ionizing radiation caused ATM activation in HNSCC cells, but high-level ULBP1 expression was not induced by gamma radiation or UV radiation. Thus, ATM/ATR signaling was neither necessary nor sufficient for high-level ULBP1 expression in human HNSCC cell lines and could not account for the proteasome effect. The selective induction of ULBP1 expression by proteasome inhibitor drugs, along with variable NKG2D ligand expression by human tumor cells, indicates that NKG2D ligand genes are independently regulated.
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影响因子：
11.2
作者：
DeYoung, Maurice Phillip;Johannessen, Cory M.;Ellisen, Leif W.
通讯作者：
Ellisen, Leif W.
影响因子：
100.3
作者：
Eagle, Robert A.;Trowsdale, John
通讯作者：
Trowsdale, John
影响因子：
2.6
作者：
Adema, AD;Cloos, J;Bryant, PE
通讯作者：
Bryant, PE
DOI：
10.1073/pnas.201238598
发表时间：
2001-09-25
影响因子：
11.1
作者：
Cerwenka, A;Baron, JL;Lanier, LL
通讯作者：
Lanier, LL
影响因子：
32.4
作者：
Cosman, D;Müllberg, J;Chalupny, NJ
通讯作者：
Chalupny, NJ