The cJUN NH(2)-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation.
The cJUN NH(2)-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation.
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DOI：
10.7554/elife.36389
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发表时间：
2018-06-01
期刊：
影响因子：
7.7
通讯作者：
Davis RJ
中科院分区：
文献类型：
--
作者：
Girnius N;Edwards YJ;Garlick DS;Davis RJ
乳腺癌是女性最常见的恶性肿瘤。乳腺癌基因组DNA的分析表明，cJUN NH 2-末端激酶（JNK）信号通路的组分中经常发生功能缺失突变。由于JNK信号传导可以通过激活AP 1转录因子来促进细胞增殖，因此JNK信号传导减少与肿瘤发展的这种明显关联是出乎意料的。我们研究了JNK缺乏对小鼠乳腺上皮细胞的影响。JNK信号转导的缺失导致基因组不稳定和乳腺癌的发展。此外，JNK缺陷导致广泛的早期肿瘤和快速肿瘤形成的小鼠模型中的乳腺癌。这种肿瘤抑制功能不是由JNK在已建立的肿瘤生长中的作用介导的，而是由JNK防止肿瘤起始的需要介导的。总之，这些数据将JNK途径缺陷鉴定为促进基因组不稳定性和肿瘤起始的“驱动”突变。随着我们体内细胞的生长和分裂，它们的DNA可能会发生变化或损坏。大多数这些“突变”是无害的，或者很快被身体修复。然而，有时突变会引发一系列遗传事件，驱使细胞不受控制地繁殖，从而导致肿瘤。识别这些“驱动突变”是复杂的，但关键是要了解癌症是如何开始的，以及如何对抗。乳腺癌是世界范围内女性中最常见的癌症类型。大型研究集中在对癌性乳腺细胞的DNA进行测序，以试图识别引发癌症的突变。结果表明，在这些细胞中，一种称为JNK信号通路的生物学机制通常被灭活，因为突变会影响参与这一过程的分子。就像链式反应一样，JNK通路中的蛋白质相互作用，直到最后一个称为JNK的蛋白质被打开。然后，该蛋白质继续参与许多细胞过程，如DNA修复。有没有可能这条途径的突变实际上会导致癌症，如果是这样，如何？Girnius等人通过灭活小鼠乳腺细胞中的JNK通路解决了这些问题。在接下来的一年半里，JNK缺陷小鼠比正常小鼠更容易患乳腺癌。进一步的实验表明，在乳腺细胞中，JNK蛋白可以防止肿瘤的出现。然而，一旦肿瘤出现，它就不能有效地阻止它们生长。没有JNK蛋白的乳腺癌细胞的DNA也包含更多的遗传变化和错误。这表明JNK信号通路有助于保持遗传信息“健康”。这可能是因为，正常情况下，JNK蛋白激活修复DNA突变的过程。总之，Girnius等人提出的结果表明，抑制JNK通路的遗传变化可以驱动乳腺癌的发展。某些抗癌药物通过破坏癌细胞的DNA来杀死癌细胞。JNK通路不活跃的乳腺肿瘤细胞修复其遗传信息的能力较低，因此这些药物可能对它们有很好的作用。未来的实验将需要验证这一假设。
Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor suppressive function was not mediated by a role of JNK in the growth of established tumors, but by a requirement of JNK to prevent tumor initiation. Together, these data identify JNK pathway defects as ‘driver’ mutations that promote genome instability and tumor initiation. As cells in our body grow and divide, their DNA can experience changes or damage. Most of these ‘mutations’ are harmless, or quickly fixed by the body. Yet, sometimes a mutation can trigger a chain of genetic events that drives the cells to multiply uncontrollably, which leads to tumors. Identifying these ‘driver mutations’ is complex, but key to understanding how cancers start and can be fought. Breast cancer is the most common type of cancer diagnosed in women worldwide. Large studies have focused on sequencing the DNA of cancerous breast cells to try to identify the mutations that started the cancer. Results show that, in these cells, a biological mechanism called the JNK signaling pathway is often inactivated because mutations affect the molecules that take part in this process. Like a chain reaction, the proteins of the JNK pathway act on each other until the last one, called JNK, gets switched on. This protein then goes on to participate in a number of cellular processes such as DNA repair. Is it possible that mutations in this pathway actually drive cancer, and if so, how? Girnius et al. addressed these questions by inactivating the JNK pathway in the breast cells of mice. Over the next year and a half, the JNK-deficient animals were more likely to get breast cancer than normal mice. Further experiments showed that, in breast cells, the JNK protein prevented tumors from appearing. However, once the tumors were present, it was less effective at stopping them from growing. The DNA of the breast cancer cells with no JNK protein also contained more genetic changes and mistakes. This suggests that the JNK signaling pathway helps to keep the genetic information ‘healthy’. This may be because, normally, the JNK protein activates processes that fix DNA mutations. Taken together, the results presented by Girnius et al. show that genetic changes which inactivate the JNK pathway can drive the development of breast cancer. Certain anti-cancer drugs kill cancerous cells by damaging their DNA. Breast tumor cells with inactive JNK pathways are less able to repair their genetic information, and so these drugs could potentially work well on them. Future experiments will be needed to test this hypothesis.