ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether-Induced Tuberous Sclerosis Renal Cell Carcinoma
ERK Crosstalks with 4EBP1 to Activate Cyclin D1 Translation during Quinol-Thioether-Induced Tuberous Sclerosis Renal Cell Carcinoma
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DOI：
10.1093/toxsci/kfr203
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发表时间：
2011-11-01
影响因子：
3.8
通讯作者：
Lau, Serrine S.
中科院分区：
文献类型：
--
作者：
Cohen, Jennifer D.;Gard, Jaime M. C.;Lau, Serrine S.
哺乳动物雷帕霉素靶蛋白（mTOR）和丝裂原活化蛋白激酶信号级联与许多人类癌症有关。肿瘤抑制基因结节性硬化症-2（Tsc-2）作为mTOR的负调节因子发挥作用。两种途径中的关键蛋白质在用肾致癌物2，3，5-三-（谷胱甘肽-S-基）氢醌（TGHQ）处理Eker大鼠（Tsc-2（EK/+））后被激活，这也导致肾肿瘤前病变和肿瘤中Tsc-2的野生型等位基因的丢失。用TGHQ处理Tsc-2（EK/+）大鼠8个月后形成的肾肿瘤的Western印迹分析显示B-Raf、Raf-1、pERK、细胞周期蛋白D1、4 EBP 1和p-4 EBP 1-Ser 65、-Thr 70和-Thr 37/46表达增加。在TGHQ介导的来源于Tsc-2（EK/+）大鼠的原代肾上皮细胞（喹啉-硫醚大鼠肾上皮[QTRRE]细胞）的转化后观察到类似的变化，所述原代肾上皮细胞也不含结核菌素。这些细胞表现出高ERK、B-Raf和Raf-1激酶活性，并增加所有p-4 EBP 1和细胞周期蛋白D1的表达。用Raf激酶抑制剂索拉非尼或MEK 1/2激酶抑制剂PD 98059处理QTRRE细胞，使所有p-4 EBP 1和细胞周期蛋白D1的蛋白表达显著降低。siRNA敲低Raf-1后，Western印迹分析显示Raf-1、细胞周期蛋白D1和上述所有p-4 EBP 1形式显著减少。相反，siRNA敲低B-Raf导致这些蛋白质的标称变化。这些数据表明Raf-1/MEK/ERK参与了与4 EBP 1的串扰，这代表了导致蛋白质合成增加、细胞生长和肾肿瘤形成的新途径相互作用。
The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase signaling cascades have been implicated in a number of human cancers. The tumor suppressor gene tuberous sclerosis-2 (Tsc-2) functions as a negative regulator of mTOR. Critical proteins in both pathways are activated following treatment of Eker rats (Tsc-2(EK/+)) with the nephrocarcinogen 2,3,5-tris-(glutathion-S-yl)hydroquinone (TGHQ), which also results in loss of the wild-type allele of Tsc-2 in renal preneoplastic lesions and tumors. Western blot analysis of kidney tumors formed following treatment of Tsc-2(EK/+) rats with TGHQ for 8 months revealed increases in B-Raf, Raf-1, pERK, cyclin D1, 4EBP1, and p-4EBP1-Ser65, -Thr70, and -Thr37/46 expression. Similar changes are observed following TGHQ-mediated transformation of primary renal epithelial cells derived from Tsc-2(EK/+) rats (quinol-thioether rat renal epithelial [QTRRE] cells) that are also null for tuberin. These cells exhibit high ERK, B-Raf, and Raf-1 kinase activity and increased expression of all p-4EBP1s and cyclin D1. Treatment of the QTRRE cells with the Raf kinase inhibitor, sorafenib, or the MEK1/2 kinase inhibitor, PD 98059, produced a significant decrease in the protein expression of all p-4EBP1s and cyclin D1. Following siRNA knockdown of Raf-1, Western blot analysis revealed a significant decrease in Raf-1, cyclin D1, and all p-4EBP1 forms noted above. In contrast, siRNA knockdown of B-Raf resulted in a nominal change in these proteins. The data indicate that Raf-1/MEK/ERK participates in crosstalk with 4EBP1, which represents a novel pathway interaction leading to increased protein synthesis, cell growth, and kidney tumor formation.