p53基因既能阻止細(xì)胞生長又能激發(fā)細(xì)胞凋亡,,p53在二者間是如何進(jìn)行選擇的呢?Thomas Jefferson大學(xué)Kimmel癌癥中心的研究人員最近發(fā)現(xiàn)了一種激活p53基因,、防止受損細(xì)胞向癌癥發(fā)展的新途徑,,對于研發(fā)化療藥物有重要的提示作用。
Jefferson醫(yī)學(xué)院癌癥生物學(xué)副教授Steven McMahon說,,p53基因/蛋白或者誘導(dǎo)受損細(xì)胞停止生長,,或者通過開啟靶標(biāo)基因啟動細(xì)胞的自殺程序。McMahon與其同事發(fā)現(xiàn)細(xì)胞的DNA受損后,,p53蛋白與DNA結(jié)合的能力受到影響,。兩種酶——hMOF和TIP60,可以改變結(jié)合位點(diǎn)賴氨酸120,,既而影響p53蛋白判斷靶標(biāo)基因的能力,。氨基酸替換,瞬時(shí)抑制p53的能力,,引起受損細(xì)胞啟動自殺程序,,盡管p53蛋白仍能停止細(xì)胞生長,這為p53蛋白的選擇機(jī)制提供了一種解釋,。研究結(jié)果刊登于《Molecular Cell》雜志,。
“p53能夠誘導(dǎo)細(xì)胞周期停滯或者凋亡(程序性細(xì)胞死亡),成為一種消除細(xì)胞損傷向癌細(xì)胞發(fā)展的方法,,不清楚的是這種選擇是怎樣完成的” McMahon說,。
新的發(fā)現(xiàn)有助于藥物研發(fā)。“大多數(shù)化療策略都將目標(biāo)鎖定在致癌細(xì)胞死亡上,,弄清p53控制細(xì)胞周期的途徑非常重要。”共同作者Stephen Sykes說鑒于p53可以決定采取哪條途徑,,有助于我們觀察p53在何種組織中更易發(fā)揮何種功能,。“比如,K120(賴氨酸120)突變引起前列腺癌,,但很少引起淋巴癌等免疫系統(tǒng)癌癥,,說明p53在某些組織中更易引起細(xì)胞死亡。”
英文原文:
Jefferson scientists find guardian gene's choices crucial to stopping cancer process
Scientists at the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have uncovered a novel pathway by which the anti-cancer gene p53 springs into action, protecting a damaged cell from becoming cancer. The gene can either halt the cell's growth or send it spiraling toward certain death. How this choice is made, the researchers say, could have implications for future strategies in chemotherapy drug development.
According to Steven McMahon, Ph.D., associate professor of cancer biology at Jefferson Medical College, who led the work, the p53 gene's – or rather its protein's – ability to direct a damaged cell to either stop growing or commit suicide depends on turning on separate groups of target genes. He and his co-workers have found that after a cell's DNA is damaged, the p53 protein's ability to bind to the DNA can be affected. Two enzymes, hMOF and TIP60, can chemically alter an amino acid, lysine 120, at the binding site, in turn influencing p53's decision on which target genes to turn on. The alteration can short-circuit p53's ability to cause the damaged cell to commit suicide, though it can still stop cell growth, suggesting that this change may help explain a mechanism behind p53's choice. They report their findings in the journal Molecular Cell.
"It's been known that p53 can induce cell cycle arrest or apoptosis (programmed cell death) as a way of eliminating developing cancer cells in response to cell damage, but no one has known how the choice is made," says Dr. McMahon. "This work narrows how the decision is made."
The findings could have implications for future drug development strategies. "Most chemotherapy strategies are aimed at getting cancer cells to die," Dr. McMahon says. "Figuring out what pathways p53 uses to cause that versus cell cycle arrest is important. It looks like this new modification that we have identified helps p53 make that decision."
"p53 is such an important player in the cancerous process – it's nearly always mutated or inactivated in cancer – that continuing to understand more about how it works will likely have significant implications for cancer research," says Dr. McMahon. "We wouldlike to understand the interplay between this newly identified pathway and others involved in p53 and cancer.
"Since p53 can make this decision, this might give some insight into which function of p53 is more important in which tissues," says co-author Stephen Sykes, a Ph.D. candidate at the University of Pennsylvania. "For example, K120 (lysine 120) mutations cause tumors in the prostate, but are not so much involved in causing immune system cancers such as lymphomas. That could suggest that p53's potential to cause cell death could be more important in certain tissues than in others. In the future, if someone could develop therapies that could specifically activate p53's potential to drive programmed cell death versus the cell cycle arrest potential, it might influence how a doctor might choose to treat a certain type of cancer.
"This may potentially enable the development of a cancer drug that would stimulate the enzymes to promote this modification driving p53 to apoptosis."