Bach1 is critical for the transformation of mouse embryonic fibroblasts by RasV12 and maintains ERK signaling
Bach1 is critical for the transformation of mouse embryonic fibroblasts by RasV12 and maintains ERK signaling
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DOI：
10.1038/onc.2012.336
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发表时间：
2013-07-04
期刊：
影响因子：
8
通讯作者：
Igarashi, K.
中科院分区：
文献类型：
--
作者：
Nakanome, A.;Brydun, A.;Igarashi, K.
活性氧（ROS），有氧呼吸的副产物，促进遗传不稳定性，并有助于细胞的恶性转化。在与ROS代谢相关的基因中，Bach 1是氧化应激反应的阻遏物，并且在高等真核生物中是由p53指导的ROS诱导的细胞衰老的负调节因子。虽然ROS密切参与致癌作用，但尚不清楚Bach 1是否参与这一过程。我们发现，衰老的Bach 1缺陷小鼠胚胎成纤维细胞（MEFs）进行自发永生化的野生型细胞一样。当用组成型活性Ras（H-Ras（V12））转导时，这些细胞在体外的增殖和集落形成显著降低。当移植到无胸腺裸鼠中时，来自Bach 1缺陷细胞的肿瘤的生长和血管化也减少。MEFs的基因表达谱揭示了一个新的H-Ras（V12）签名，这是不同于以前报道的上皮肿瘤的签名，部分依赖于Bach 1。Bach 1缺陷细胞显示MEK和ERK 12的磷酸化响应于H-Ras（V12）减少，这与基因表达谱（包括磷酸酶基因）的改变一致。最后，Bach 1缺陷小鼠对4-硝基喹啉-1-氧化物（4-NQO）诱导的舌癌的敏感性低于野生型小鼠。我们的数据为Bach 1在活化的H-Ras（V12）诱导的细胞转化和肿瘤生长中的关键作用提供了证据。
Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, Bach1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether Bach1 is involved in this process. We found that senescent Bach1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-Ras(V12)), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from Bach1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-Ras(V12) signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on Bach1. The Bach1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-Ras(V12), which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, Bach1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of Bach1 in cell transformation and tumor growth induced by activated H-Ras(V12).