2012年5月3日,，人體會(huì)不斷產(chǎn)生新的細(xì)胞來(lái)取代死去的細(xì)胞,，但這一過(guò)程并非十全十美,。細(xì)胞間需要溝通或示意對(duì)方來(lái)決定何時(shí)生成新的細(xì)胞。細(xì)胞內(nèi)的通信或信號(hào)錯(cuò)誤通常導(dǎo)致細(xì)胞生長(zhǎng)失控,，這喲過(guò)程是許多癌癥發(fā)生的基礎(chǔ),。
得克薩斯大學(xué)休斯敦（UTHealth）醫(yī)學(xué)院健康科學(xué)中心科學(xué)家們發(fā)現(xiàn)了能對(duì)抗黑色素瘤皮膚癌和其他某些腫瘤快速蔓延的有關(guān)的細(xì)胞信號(hào)。
科學(xué)家報(bào)告說(shuō),，他們已經(jīng)發(fā)現(xiàn)為什么一類稱為BRAF抑制劑被廣泛用于治療黑色素瘤的藥物并不總是發(fā)揮作用,，最重要的是明確了這些藥物是如何加速某些病人的癌癥增長(zhǎng)的?？茖W(xué)家們的研究結(jié)果發(fā)表在Cell Press出版的Current Biology雜志上,。
John Hancock博士說(shuō)：此研究可能有助于更有效的發(fā)展抗癌藥物，并更好地了解新的藥物組合的選擇,。
生長(zhǎng)信號(hào)從細(xì)胞表面?zhèn)鬏數(shù)郊?xì)胞核,，形成了一個(gè)信號(hào)通路。細(xì)胞分裂產(chǎn)生新細(xì)胞的命令是由四個(gè)蛋白質(zhì)鏈（Ras→BRAF→MEK→ERK）執(zhí)行的,。所有的細(xì)胞都有這個(gè)途徑,，大部分時(shí)間內(nèi)并事能有效工作產(chǎn)生新的細(xì)胞。
當(dāng)鏈中的兩種蛋白質(zhì)之一發(fā)生了突變時(shí)問(wèn)題產(chǎn)生了,，好消息是醫(yī)生有阻斷BRAF的蛋白質(zhì)藥物,。這就是BRAF抑制劑，能成功治療BRAF蛋白突變的黑色素瘤,。
那么不好的消息是,，醫(yī)生不能阻止第一蛋白的Ras信號(hào)。因此，研究人員研究了當(dāng)運(yùn)用BRAF抑制劑時(shí),，體內(nèi)發(fā)生了什么變化,。
令人驚訝的是，BRAF抑制劑不阻止黑色素瘤細(xì)胞的ras基因突變,。事實(shí)上,，藥物提高了異常信號(hào)活動(dòng)。研究的主要作者說(shuō),，我們現(xiàn)在的工作介紹了這個(gè)看似矛盾的增強(qiáng)信號(hào)活動(dòng)的機(jī)制,。
從病人身上分離出的最惡性黑色素瘤有一個(gè)BRAF或ras基因突變，但很少有兩個(gè),。 ras基因突變導(dǎo)致其他正常的BRAF蛋白接通聯(lián)系起來(lái),。
我們的研究還強(qiáng)調(diào)使用BRAF抑制劑前，黑色素瘤基因檢測(cè)的重要性,。 Cho說(shuō),，我們的研究可能還有助于設(shè)計(jì)出更好的藥物。（生物谷：Bioon.com)
doi:10.1016/j.cub.2012.03.067
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Raf Inhibitors Target Ras Spatiotemporal Dynamics
Kwang-jin Cho, Rinshi S. Kasai, Jin-Hee Park, Sravanthi Chigurupati, Sonja J. Heidorn, Dharini van der Hoeven, Sarah J. Plowman, Akihiro Kusumi, Richard Marais, John F. Hancock
Background
The lateral segregation of Ras proteins into transient plasma membrane nanoclusters is essential for high-fidelity signal transmission by the Ras mitogen-activated protein kinase (MAPK) cascade. In this spatially constrained signaling system, the dynamics of Ras nanocluster assembly and disassembly control MAPK signal output.
Results
We show here that BRaf inhibitors paradoxically activate CRaf and MAPK signaling in Ras transformed cells by profoundly dysregulating Ras nanocluster dynamics. Specifically, BRaf inhibitors selectively enhance the plasma membrane nanoclustering of oncogenic K-Ras and N-Ras but have no effect on H-Ras nanoclustering. Raf inhibitors are known to drive the formation of stable BRaf-CRaf and CRaf-CRaf dimers. Our results demonstrate that the presence of two Ras-binding domains in a single Raf dimer is sufficient and required to increase Ras nanoclustering, indicating that Raf dimers promote K- and N-Ras nanocluster formation by crosslinking constituent Ras proteins. Ras crosslinking increases the fraction of K-Ras and N-Ras in their cognate nanoclusters, leading to an increase in MAPK output from the plasma membrane. Intriguingly, increased MAPK signaling in BRaf inhibited cells is accompanied by significantly decreased Akt activation. We show that this signal pathway crosstalk results from a novel mechanism of competition between stabilized Raf dimers and p110α for recruitment to Ras nanoclusters.
Conclusions
Our findings reveal that BRaf inhibitors disrupt Ras nanocluster dynamics with significant, yet divergent, consequences for MAPK and PI3K signaling.
