最近費城Wistar研究所和奧地利Vienna生物中心的研究人員鑒別出一種與p53蛋白的正常抑癌功能相關(guān)的新機制,。研究結(jié)果刊登于11月15日電子版Nature。
文章高級作者,、Wistar 研究所Hilary Koprowski教授說p53蛋白在肌體內(nèi)作用重大,，能夠控制癌癥，“我們發(fā)現(xiàn)的新機制,，主要涉及到一種從未被報道過的酶,，當(dāng)肌體不再需要p53蛋白發(fā)揮作用時能夠抑制p53蛋白的活性。”
“我們所關(guān)心的是這些酶過表達,、過活化,，就有可能抑制p53蛋白正常的腫瘤抑制功能，進而引發(fā)癌癥,。如果真是這樣,，我們就可以設(shè)計一種藥物，抑制此酶的活性,，釋放p53蛋白讓它去完成抑制腫瘤的工作,。此酶表達水平過高,，也許可以成為一種癌癥診斷標(biāo)志。”
p53蛋白于肌體各處發(fā)揮抑制腫瘤的功效,，在一半以上的人類癌癥中都有發(fā)現(xiàn)p53蛋白突變或者功能障礙,。正常情況下，p53與目的DNA結(jié)合,，抑制DNA損傷的細胞分裂直到損傷被修復(fù)為止,。癌癥細胞也發(fā)生類似DNA損傷，所有癌癥的遺傳物質(zhì)都會發(fā)生遺傳或后天產(chǎn)生的缺陷,，如果損傷不能得到及時修復(fù),，p53蛋白會要求此細胞凋亡，以防止它禍害肌體其它部位,。
p53蛋白這種抑制細胞分裂,、誘導(dǎo)細胞自殺的能力也是利用抑制機制，比如新研究中所強調(diào)的細胞存活的關(guān)鍵,。
“可以試想一下,，如果p53蛋白始終存在，隨時準(zhǔn)備與DNA結(jié)合,，那么細胞將會面臨大麻煩,，”
Berger說，“細胞不能分裂,，它們會死亡,。我們發(fā)現(xiàn)的新機制能夠在p53蛋白存在的條件下關(guān)閉p53蛋白的活性，在DNA受損時及時恢復(fù)p53蛋白的活性,。”
Berger等所發(fā)現(xiàn)的途徑的關(guān)鍵酶叫做Smyd2,，Smyd2向p53蛋白的特異位點添加一個甲基基團，導(dǎo)致p53蛋白不能與DNA結(jié)合而發(fā)揮作用,。“與DNA結(jié)合對p53蛋白正常發(fā)揮功能至關(guān)重要,，”另一位論文作者黃京（Jing Huang，音譯）博士說,，“我們發(fā)現(xiàn)Smyd2作用位點的甲基化能夠抑制p53蛋白與DNA結(jié)合,，也能夠解釋為什么甲基化是一種抑制修飾。”
Berger和黃強調(diào)這是在組蛋白以外蛋白中,，發(fā)現(xiàn)甲基化能夠調(diào)節(jié)蛋白活性的少數(shù)實驗之一,。真核細胞DNA和組蛋白緊密地包裝在一起，形成核小體（構(gòu)成染色質(zhì)的基本單位）,。對于組蛋白而言,，甲基化已經(jīng)被證明是一個很好的調(diào)節(jié)機制，實際上對其它蛋白來說,，甲基化則是相對較新的研究領(lǐng)域,。Berger認為今后五年內(nèi)，在其它蛋白系統(tǒng)的研究中應(yīng)該陸續(xù)有甲基化調(diào)節(jié)機制的報道出現(xiàn),。
有趣的是除了Berger意外,，關(guān)于甲基化調(diào)節(jié)p53蛋白活性的研究，還有一次報道,。該報道中,，研究人員向p53蛋白K372位點添加甲基化基團，發(fā)現(xiàn)p53蛋白的腫瘤抑制活性不但沒有下降,，反而上升了（這與Smyd2作用位點甲基化效果恰恰相反）,。K372位點目前正在研究過程中。K372與Berger和黃等發(fā)現(xiàn)的位點接近,，附加實驗發(fā)現(xiàn)這兩個位點相互作用緊密,。
“我們發(fā)現(xiàn)這兩個位點之間聯(lián)系緊密，但只是單向通話,，”黃說,，“如果先前報道的位點已經(jīng)被甲基化了，那么我們發(fā)現(xiàn)的位點就不能再被甲基化,，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."
