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　　近日，美國沙克生物研究所（Salk Institute for Biological Studies）的研究人員發(fā)現(xiàn)感冒病毒（cold virus）產(chǎn)生的一種小分子蛋白E4-ORF3可破壞與生長、復(fù)制和癌癥有關(guān)的細(xì)胞器。這種蛋白可在細(xì)胞核中形成三維網(wǎng)狀結(jié)構(gòu)，捕獲目標(biāo)細(xì)胞器。這一發(fā)現(xiàn)為癌癥的治療開辟了一條新的道路，相關(guān)論文發(fā)表在10月11日的《Cell》雜志上。

　　E4-ORF3是腺病毒編碼的一種致癌蛋白，它可組阻止腫瘤抑制蛋白p53與其靶基因的結(jié)合。P53被認(rèn)為是基因組衛(wèi)士（guardian of the genome），在正常情況下可通過使DNA發(fā)生損傷的細(xì)胞自我毀滅而抑制腫瘤的發(fā)生。在幾乎所有類型的人類癌癥中，p53的腫瘤抑制作用都喪失，使得癌細(xì)胞逃脫正常的生長控制。E4-ORF3可抑制p53，使得腺病毒可以在感染的人類細(xì)胞中進(jìn)行復(fù)制。

　　研究的領(lǐng)導(dǎo)者Clodagh O'Shea說，癌癥是一個黑匣子，弄清楚小DNA腫瘤病毒（DNA tumor virus）蛋白和細(xì)胞的腫瘤抑制復(fù)合體（tumor suppressor complexes）之間的相互作用才能找到黑匣子的鑰匙。但若不清楚這種蛋白質(zhì)的結(jié)構(gòu)，我們便無法理解為何它可勝過腫瘤抑制基因。

　　兩年前，O'Shea發(fā)現(xiàn)E4-ORF3可為腺病毒的增殖鋪平道路，這一作用通過抑制幫助細(xì)胞抵御這一病毒的基因?qū)崿F(xiàn)。E4-ORF3可在細(xì)胞中自組裝稱無序、網(wǎng)狀結(jié)構(gòu)，繼而捕獲并滅活腫瘤抑制蛋白。

　　此外，研究者解析了E4-ORF3在細(xì)胞核中形成的聚合物的超微結(jié)構(gòu)。這項研究成果可幫助科學(xué)家開發(fā)新的小分子藥物，這種藥物通過結(jié)合并擾亂幫助癌細(xì)胞生長和擴(kuò)散的細(xì)胞元件發(fā)揮作用。

　　為避免殺死健康細(xì)胞需設(shè)計"腫瘤爆炸病毒"（tumor-busting virus），這種改造的病毒僅可破壞癌細(xì)胞，因其僅能在p53受抑制的癌細(xì)胞中復(fù)制。當(dāng)一個癌細(xì)胞被殺死，它可釋放出已復(fù)制的病毒，然后尋找并殺死擴(kuò)散至全身的癌細(xì)胞。

　　設(shè)計這種病毒需要使得E4-ORF3失去滅活正常細(xì)胞p53的作用，否則E4-ORF3在殺死癌細(xì)胞的同時也殺死了正常細(xì)胞。
 

　　Cold viruses point the way to new cancer therapies

　　Horng D. Ou1, Witek Kwiatkowski2, Thomas J. Deerinck5, Andrew Noske5, Katie Y. Blain2, Hannah S. Land3, Conrado Soria1, Colin J. Powers1, Andrew P. May10, Xiaokun Shu7, 8, 11, Roger Y. Tsien7, 8, 9, James A.J. Fitzpatrick4, Jeff A. Long3, Mark H. Ellisman5, 6, Senyon Choe2, Clodagh C. O'Shea

　　Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a central β core, and its structure is unrelated to known polymers or oncogenes. E4-ORF3 dimer units coassemble through reciprocal and nonreciprocal exchanges of their C-terminal tails. This results in linear and branched oligomer chains that further assemble in variable arrangements to form a polymer network that partitions the nuclear volume. E4-ORF3 assembly creates avidity-driven interactions with PML and an emergent MRN binding interface. This reveals an elegant structural solution whereby a small protein forms a multivalent matrix that traps disparate tumor suppressors.

　　Salk researchers discovered that a small protein produced by cold viruses disables large cellular machines involved in growth, replication and cancer. These proteins accomplish this by forming a three-dimensional web inside a cell's nucleus (yellow) that traps these components. The findings point the way to new ways to target and destroy tumors. Credit: Salk Institute for Biological Studies

　　Cold viruses generally get a bad rap—which they've certainly earned—but new findings by a team of scientists at the Salk Institute for Biological Studies suggest that these viruses might also be a valuable ally in the fight against cancer.

　　Adenovirus, a type of cold virus, has developed molecular tools—proteins—that allow it to hijack a cell's molecular machinery, including large cellular machines involved in growth, replication and cancer suppression. The Salk scientists identified the construction of these molecular weapons and found that they bind together into long chains (polymers) to form a three-dimensional web inside cells that traps and overpowers cellular sentries involved in growth and cancer suppression. The findings, published October 11 in Cell, suggest a new avenue for developing cancer therapies by mimicking the strategies employed by the viruses.

　　"Cancer was once a black box," says Clodagh O'Shea, an assistant professor in Salk's Molecular and Cell Biology Laboratory, who led the study. "The key that opened that box was revealing the interactions between small DNA tumor virus proteins and cellular tumor suppressor complexes. But without knowing the structure of the proteins they use to attack cells, we were at a loss for how these tiny weapons win out over much larger tumor suppressors."

　　O'Shea's team studied E4-ORF3, a cancer-causing protein encoded by adenovirus, which prevents the p53 tumor suppressor protein from binding to its target genes. Known as the "guardian of the genome," p53 normally suppresses tumors by causing cells with DNA damage—a hallmark of cancer—to self-destruct. The p53 tumor suppressor pathway is inactivated in almost every human cancer, allowing cancer cells to escape normal growth controls. Similarly, by inactivating p53, the E4-ORF3 protein enables adenovirus replication in infected human cells to go unchecked.

　　E4-ORF3 self-assembles inside cells into a disordered, web-like structure that captures and inactivates different tumor suppressor protein complexes. Horng Ou, a postdoctoral researcher in O'Shea's laboratory, says E4-ORF3 is unusual. "It doesn't resemble any known proteins that assemble polymers or that function in cellular tumor suppressor pathways," he says. "Most cellular polymers and filaments form uniform, rigid chains. But E4-ORF3 is the virus's Swiss army knife—it assembles into something that is highly versatile. It has the ability to build itself into all sorts of different shapes and sizes that can capture and deactivate the many defenses of a host cell."

　　In collaboration with scientists from the National Center for Microscopy and Imaging Research at University of California, San Diego, led by Mark Ellisman, the center's director, O'Shea's team used new techniques to reveal the ultrastructure of the remarkable polymer that E4-ORF3 assembles in the nucleus—something that previously had proven difficult since the polymer is effectively invisible using conventional electron microscopy. "What you see is the E4-ORF3 polymer bending and weaving and twisting its way through the nucleus," she says. "It does appear to have a single repeating pattern and creates a matrix that captures several different tumor suppressors and silences p53 target genes."

　　Initially, E4-ORF3 forms a dimer, made up of only two subunits. In this form, E4-ORF3 largely ignores its cellular targets. The researchers theorized that when E4-ORF3 assembles into a polymer, however, it binds to tumor suppressor targets far more aggressively. To test this theory, they genetically fused E4-ORF3 polymer mutants to lamin, a cellular protein that assembles intermediate filaments that provide stability and strength to cells. They showed that the lamin-E4-ORF3 fusion protein assembled into cylinder-like superstructures in the nucleus that bind and disrupt PML, a protein complex that suppresses tumors.

　　The Salk findings may help scientists develop small molecules—the basis for the vast majority of current drugs—capable of destroying tumors by binding and disrupting large and complex cellular components that allow cancer cells to grow and spread. Understanding how viruses overcome healthy cells may also help scientists engineer tumor-busting viruses, which offer a new and potentially self-perpetuating cancer therapy. Such modified viruses would destroy only cancer cells, because they could only replicate in cells in which the p53 tumor suppressor has been deactivated. When a cancer cell is destroyed it would release additional copies of the engineered viruses, which would seek out and kill remaining cancer cells that have spread throughout the body.

　　Engineering these viruses requires disabling the ability of the E4-ORF3 protein to inactivate p53 in healthy cells—otherwise, the virus could destroy healthy cells as well as cancer cells. At the same time, E4-ORF3 has certain important functions in allowing the virus to replicate in the first place, so it can't be completely removed from the virus's arsenal. Thus, the Salk researcher's work on understanding the protein's precise structure, functions and interactions is crucial to engineering viruses in which E4-ORF3's abilities have been precisely modified.