NCI科学家发现蛋白分子伴侣的分子开关

NCI 科学家发现蛋白分子伴侣的分子开关

根据一项最新的对热休克蛋白90（Hsp90）最新的研究，一种扮演着其他蛋白质分子伴侣角色的蛋白质需要经过特殊的化学修饰才能发挥其正常功能，而这种伴侣蛋白质在控制正常细胞生长和促进肿瘤细胞发育中起着重要作用。该研究是由国立卫生研究院（NIH ）的分支机构国立癌症研究所（NCI ）同其他几家研究机构合作完成，文章发表在2007年1月12日的《分子细胞》杂志上。

NCI 所长John E. Niederhuber博士说：“这一新鉴定出的细胞调节Hsp90活性的方式，可能有助于我们更好的了解更多关于在肿瘤发生过程中基础细胞信号途径的变化，并且有希望找到新的抗肿瘤治疗靶点。”

大部分蛋白质在合成之后，必须折叠而成它们最后的形态已发挥正常功能。Hsp90作为其他蛋白质的分子伴侣，通过帮助它们折叠并护送它们到达细胞内适当的位置来完成这一过程。已经发现了有100多种作为Hsp90“顾客”的蛋白质。在应激情况下，Hsp90产物急剧增加以帮助重折叠或清楚损伤的蛋白质，从而帮助细胞恢复正常状态并提高其生存能力。Hsp90水平在多种肿瘤细胞中升高。Hsp90结合有助于维持某些顾客蛋白质的致癌性突变，使得细胞脱离生长调控并发展成肿瘤。以往的研究显示Hsp90的化学抑制剂有助于阻断细胞分裂、促进细胞自杀和减慢肿瘤扩散。几种不同的Hsp90抑制剂目前正在临床试验中，以测试其治疗肿瘤的效果。

NCI 癌症研究中心泌尿系肿瘤学组组长Leonard M. Neckers博士和他的同事们以往的研究显示，用组蛋白去乙酰化酶（HDAC ）抑制剂处理细胞可以获得与直接使用Hsp90抑制药物同样的效果。HDAC 可以从很多蛋白质中去除一种叫做乙酰基的化学结构。在蛋白质特定的位置添加乙酰基的过程又叫做乙酰化，这是细胞控制蛋白质活性的一种机制。HDAC 抑制剂阻断了去乙酰基化过程。当前研究的目的是明确乙酰化在调节Hsp90功能中所起的作用。

该研究小组首先明确了，当HDAC 抑制剂存在时，Hsp90是以乙酰化形式存在并且其伴侣活性被抑制。接下来，他们鉴定出了Hsp90蛋白上一个特殊乙酰化位点，并且发现这一单

个氨基酸或者说蛋白质构件可作为Hsp90的调节阀，通过在该位点添加或去除乙酰基实现其调节作用。通过在位于顾客蛋白结合区该位点制造突变，可模拟乙酰化或者去乙酰化氨基酸。然后，在人类和酵母细胞中检测了这些突变对于蛋白质功能和细胞生存能力的影响。从Hsp90上这一氨基酸位点去除乙酰基增强了该分子伴侣与其顾客分子的香花作用。反过来，乙酰化减弱了Hsp90与顾客蛋白和共分子伴侣的联系，并且改变了酵母细胞中Hsp90分子伴侣的活性。如果将上面几点综合考虑，该证据表明乙酰化状态是Hsp90伴侣—顾客分子相互作用的一个关键因素。

“这些结果让我们能够更好的理解，为何通过抑制去乙酰化促进Hsp90乙酰化可能是一个抑制肿瘤细胞生长的好方法，” Neckers说：“现在我们可以开始考虑联合HDAC 抑制剂与Hsp90化学抑制剂来治疗癌症了。”

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NCI Researchers Identify Molecular Switch for Protein Chaperone

A protein that plays a major role in controlling normal cell growth and promoting tumor

development by acting as a chaperone to other proteins was found to require a specific chemical modification for normal function, according to a new study of heat shock protein 90 (Hsp90). This research was conducted at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), in collaboration with other institutions* and appears in the January 12, 2007, issue of Molecular Cell**.

"This new appreciation for the way cells regulate Hsp90 activity may help us better understand more of the basic cell signal pathway alterations involved in cancer development and, hopefully, identify new targets for anticancer therapies," said NCI Director John E. Niederhuber, M.D.

After they are synthesized, most proteins must be folded into their final form in order to function normally. Hsp90 chaperones other proteins through this process by assisting in their folding and

escorting them to their proper locations inside the cell. Over 100 proteins have been identified as 'clients' of Hsp90. Under stress conditions, Hsp90 production increases sharply to assist in either refolding or elimination of damaged proteins, thereby helping cells return to a normal state and increasing their ability to survive.

Hsp90 levels are elevated in many types of cancer cells. Hsp90 binding helps sustain

cancer-causing mutations in certain client proteins, allowing the cells to escape growth regulation and develop into tumors. Previous studies have shown that chemical inhibitors of Hsp90 can help block cell division, encourage cell suicide, and reduce the spread of a tumor. Several different Hsp90 inhibitors are currently undergoing clinical trials to test their efficacy in the treatment of cancer.

Leonard M. Neckers, Ph.D., who led this study in the Urologic Oncology Branch in NCI's Center for Cancer Research, and his colleagues previously showed that treating cells with an inhibitor of the enzyme histone deacetylase (HDAC) had the same effect as directly inhibiting Hsp90 with drugs. HDAC removes certain chemicals, called acetyl groups, from a wide range of proteins. Adding acetyl groups to proteins at specific locations -- a process called acetylation -- is one mechanism cells use to control protein activity. HDAC inhibitors block the removal of these acetyl groups. The purpose of this current study was to understand the role of acetylation in regulating Hsp90 function.

The team first determined that, in the presence of HDAC inhibitors, Hsp90 is acetylated and chaperone activity is inhibited. Next, they identified a specific location on the Hsp90 protein that is acetylated and found that a single amino acid, or protein building block, acts as an Hsp90 regulator through the addition and removal of acetyl groups at that site. Mutations were made at this site, which is located in a region where client proteins bind, to mimic either an acetylated or a non-acetylated amino acid. Then, both human and yeast cells were used to determine the effects of these mutations on protein function and cell viability. The removal of an acetyl group from Hsp90 at this amino acid strengthened the interactions between the chaperone and its clients. Conversely, acetylation weakened Hsp90 association with client proteins and co-chaperones, and altered

Hsp90 chaperone activity in yeast. Taken together, this evidence suggests that acetylation status is

an important factor in Hsp90 chaperone-client interaction.

"These results give us a better understanding of why promoting Hsp90 acetylation, by inhibiting deacetylation, might be a good approach to inhibiting cancer cell growth," said Neckers. "Now we can start thinking about combining HDAC inhibitors with Hsp90 chemical inhibitors for the treatment of cancer."

文章引用自：http://www.cancer.gov/newscenter/pressreleases/HSP90