最近费城Wistar研究所和奥地利Vienna生物中心的研究人员鉴别出一种与p53蛋白的正常抑癌功能相关的新机制。研究结果刊登于11月15日电子版Nature。
文章高级作者、Wistar 研究所Hilary Koprowski教授说p53蛋白在肌体内作用重大，能够控制癌症，“我们发现的新机制，主要涉及到一种从未被报道过的酶，当肌体不再需要p53蛋白发挥作用时能够抑制p53蛋白的活性。”
“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。”
p53蛋白于肌体各处发挥抑制肿瘤的功效，在一半以上的人类癌症中都有发现p53蛋白突变或者功能障碍。正常情况下，p53与目的DNA结合，抑制DNA损伤的细胞分裂直到损伤被修复为止。癌症细胞也发生类似DNA损伤，所有癌症的遗传物质都会发生遗传或后天产生的缺陷，如果损伤不能得到及时修复，p53蛋白会要求此细胞凋亡，以防止它祸害肌体其它部位。
p53蛋白这种抑制细胞分裂、诱导细胞自杀的能力也是利用抑制机制，比如新研究中所强调的细胞存活的关键。
“可以试想一下，如果p53蛋白始终存在，随时准备与DNA结合，那么细胞将会面临大麻烦，”
Berger说，“细胞不能分裂，它们会死亡。我们发现的新机制能够在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。”
Berger等所发现的途径的关键酶叫做Smyd2，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。“与DNA结合对p53蛋白正常发挥功能至关重要，”另一位论文作者黄京（Jing Huang，音译）博士说，“我们发现Smyd2作用位点的甲基化能够抑制p53蛋白与DNA结合，也能够解释为什么甲基化是一种抑制修饰。”
Berger和黄强调这是在组蛋白以外蛋白中，发现甲基化能够调节蛋白活性的少数实验之一。真核细胞DNA和组蛋白紧密地包装在一起，形成核小体（构成染色质的基本单位）。对于组蛋白而言，甲基化已经被证明是一个很好的调节机制，实际上对其它蛋白来说，甲基化则是相对较新的研究领域。Berger认为今后五年内，在其它蛋白系统的研究中应该陆续有甲基化调节机制的报道出现。
有趣的是除了Berger意外，关于甲基化调节p53蛋白活性的研究，还有一次报道。该报道中，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Berger和黄等发现的位点接近，附加实验发现这两个位点相互作用紧密。
“我们发现这两个位点之间联系紧密，但只是单向通话，”黄说，“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，反之不然。”
英文原文：
Novel Regulatory Mechanism Identified For Key Tumor Suppressor P53
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."
