Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species
Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species
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DOI：
10.1038/onc.2009.355
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发表时间：
2010-01-01
期刊：
影响因子：
8
通讯作者：
Lee, J-S
中科院分区：
文献类型：
--
作者：
Lee, J-J;Lee, J-H;Lee, J-S
衰老被认为是防止肿瘤发生的细胞防御机制。虽然最近的证据表明c-Jun N-末端激酶（JNK）参与衰老过程，但这种调节的机制尚未完全了解。在这里，我们研究了JNK在肿瘤细胞早衰中的作用。用JNK特异性抑制剂SP 600125处理细胞引起衰老的表型变化，并引发MCF 7乳腺癌细胞中线粒体活性氧（ROS）产生和DNA损伤反应（DDR）的快速增加。ROS的产生归因于B细胞淋巴瘤-2（Bcl-2）磷酸化的抑制，并导致DNA损伤和p53激活。Bax并没有改变其定位到线粒体，这是细胞凋亡所必需的。JNK和磷酸化Bcl-2在防止早衰中的重要作用通过RNA干扰和Bcl-2突变体的异位表达得到证实，包括磷酸化和非磷酸化形式。这些发现在H460肺癌细胞和原代人胚胎成纤维细胞中得到证实。总之，我们的研究结果表明，JNK活性的丧失触发Bcl-2/ROS/DDR信号级联反应，最终导致早衰，表明基础JNK活性在预防早衰中是必不可少的。Oncogene（2010）29，561-575; doi：10.1038/onc.2009.355; 2009年10月26日在线发表
Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences show that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the mechanism for this regulation is not fully understood. Here, we examined the role of JNK in premature senescence of tumor cells. Treatment of cells with the JNK-specific inhibitor SP600125 caused phenotypical changes of senescence and triggered a rapid increase in mitochondrial reactive oxygen species (ROS) production and DNA-damage response (DDR) in MCF7 breast carcinoma cells. ROS generation was attributed to the suppression of B-cell lymphoma-2 (Bcl-2) phosphorylation, and resulted in DNA damage and p53 activation. Bax did not change their localization to the mitochondria, which is required for apoptosis. The essential roles of JNK and phosphorylated Bcl-2 in preventing premature senescence were confirmed using RNA interference and ectopic expression of mutants of Bcl-2, including phosphomimetic and nonphosphorylatable forms. These findings were evidenced in H460 lung carcinoma cells and primary human embryonic fibroblasts. Altogether, our results showed that loss of JNK activity triggers a Bcl-2/ROS/DDR signaling cascade that ultimately leads to premature senescence, indicating that basal JNK activity is essential in preventing premature senescence. Oncogene (2010) 29, 561-575; doi: 10.1038/onc.2009.355; published online 26 October 2009