来自美国宾州Wistar研究院（The Wistar Institute）基因表达和调控研究小组，和奥地利维也纳生物中心（The Vienna Biocenter）分子病理学研究院（Research Institute of Molecular Pathology，IMP)的研究人员发现了一种与p53蛋白的正常抑癌功能相关的新机制：一种新发现的酶——Smyd2能在肌体不再需要p53蛋白发挥作用时能够抑制p53蛋白的活性。这是第二次发现甲基化能调节p53蛋白活性，有趣的是第一次有关甲基化调节p53蛋白活性研究的结果与这一次的结果正好相反。这一研究成果公布在11月30日出版的《Nature》杂志上。
这一研究报告的第一作者是来自Wistar研究院的黄京（Jing Huang，音译）。
p53基因是一种肿瘤抑制基因，定位于人类17号染色体短臂，编码p53磷蛋白；p53磷蛋白的正常功能是调控细胞增殖，在白血病、骨肉瘤、肺癌和结直肠癌中有p53蛋白的突变和缺失。现在已经证明，p53蛋白是人体内最有效的对抗肿瘤的自然防御物。最近关于p53最重要的发现是：一些小分子药物可以通过阻止p53负调节子Mdm2与p53的结合来激活p53。这一研究为新的肿瘤治疗方法、通过蛋白质相互作用找到新的、有效的药物靶点提供了光明的前景，因此p53多年以来一直是肿瘤研究的热点领域。
另一方面，组蛋白赖氨酸甲基化特异性位点是调控转录激活或抑制的一个重要因素，目前所知p53是由赖氨酸甲基化调控的少见的非组蛋白之一，在这篇文章中，研究人员发现Smyd2这种赖氨酸转甲基酶可以使p53蛋白上的Lys370位点甲基化——这是从来未发现过的甲基化位点。
这对于肿瘤研究意义重大，正如Wistar 研究所Hilary Koprowski教授说的那样：“我们所关心的是这些酶过表达、过活化，就有可能抑制p53蛋白正常的肿瘤抑制功能，进而引发癌症。如果真是这样，我们就可以设计一种药物，抑制此酶的活性，释放p53蛋白让它去完成抑制肿瘤的工作。此酶表达水平过高，也许可以成为一种癌症诊断标志。”
这项研究中发现Smyd2向p53蛋白的特异位点添加一个甲基基团，导致p53蛋白不能与DNA结合而发挥作用，这也就是说Smyd2作用位点的甲基化能够抑制p53蛋白与DNA结合，解释了为什么甲基化是一种抑制修饰。
这一新机制能够在p53蛋白存在的条件下关闭p53蛋白的活性，在DNA受损时及时恢复p53蛋白的活性。这对于细胞而言意义重大，因为如果p53蛋白始终存在，随时准备与DNA结合，那么细胞就不能分裂，它们会死亡。
在之前发现的另一个甲基化调节p53蛋白活性的研究中，研究人员向p53蛋白K372位点添加甲基化基团，发现p53蛋白的肿瘤抑制活性不但没有下降，反而上升了（这与Smyd2作用位点甲基化效果恰恰相反），K372位点目前正在研究过程中。K372与目前这一Smyd2研究发现的位点接近，更多实验也发现这两个位点相互作用紧密。黄京表示：“如果先前报道的位点已经被甲基化了，那么我们发现的位点就不能再被甲基化，反之亦然。”
英文原文：
(PHILADELPHIA) – Collaborating scientists from The Wistar Institute in Philadelphia and The Vienna Biocenter in Austria have identified a novel mechanism involved in normal repression of the p53 protein, perhaps the single most important molecule for the control of cancer in humans.
The new molecular pathway described in the study suggests intriguing approaches to diagnosing or intervening in the progression of many types of cancer. A report on the team's findings will be published online November 15 in the journal Nature.
"The p53 protein is vital for controlling cancer throughout the body," says Shelley L. Berger, Ph.D., the Hilary Koprowski Professor at The Wistar Institute and senior author on the study. "The new mechanism we describe, driven by a previously unknown enzyme, represses the p53 protein when its activity is not needed.
"What we're looking at now is the possibility that this enzyme, if over-expressed or over-active, might interfere with p53's normal tumor suppressor function and perhaps cause cancer. If that's the case, then we could develop drugs to inhibit the enzyme that would have the effect of freeing p53 to do its job of suppressing cancer. Unusually high levels of the newly identified enzyme might also be useful as a diagnostic marker for cancer."
Responsible for tumor suppression throughout the body, the p53 protein has been found to be mutated and dysfunctional in more than half of human cancers. When working properly, p53 acts by binding to DNA to activate genes that direct cells with damaged DNA to cease dividing until the damage can be repaired. Cells with such damage include cancer cells, since all cancers track to genetic flaws of one kind or another, whether inherited or acquired. If repairs cannot be made, p53 commands the cells with damaged DNA to self-destruct so they are no longer a danger to the body.
This powerful ability of the p53 protein to shut down cell division and induce cell death points to why the availability of a repressive mechanism such as the one outlined in the new study might be crucial for cellular survival.
"You can imagine that if the p53 protein were present at all times and able to bind to DNA, cells would be in big trouble," Berger explains. "They wouldn't be able to divide, and they'd die. We think this new mechanism may be a way for the cell to keep p53 turned off but present, ready to be activated if the DNA should be damaged."
In their study, the scientists identified an enzyme called Smyd2 that adds a methyl group to the p53 protein at a specific site, with the result being that p53 cannot bind to DNA and, therefore, cannot act.
"The ability to bind to DNA is critical for p53's function," says Jing Huang, Ph.D., one of the study's two lead authors. "What we found was that methylation at the site we identified prevents p53 from binding to DNA, which also explains why it's a repressive modification."
Berger and Huang note that this is one of only a small number of studies to identify methylation as playing a role in regulating the activity of proteins that are not histones. Histones are relatively small proteins around which DNA is coiled to create structures called nucleosomes. Compact strings of nucleosomes, then, form into chromatin, the substructure of chromosomes.
With histones, methylation is well recognized as a regulatory mechanism, but the fact that other proteins are also be modified in the same way is a relatively new observation. Berger believes that scientists will likely find this type of regulatory mechanism at work in many other protein systems over the next few years.
Interestingly, only one other study has shown a role for methylation in regulating p53. In that study, a methyl group added to a specific site on p53 called K372 was shown to activate the tumor-suppressor molecule rather than repress it.
The site identified in the current study, dubbed K370, is adjacent to that first site. An additional finding of note is that the two sites interact closely.
"We found that there's important crosstalk between the two sites, but only in one direction," Huang says. "If the previously identified site is already methylated, the site we found cannot be methylated. But the reverse is not the case."
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