最近賓州大學(xué)醫(yī)學(xué)院研究人員鑒定出一種急性髓系白血病（acute myelogenous leukemia ,，AML）相關(guān)蛋白——Tribbles,。
Tribbles蛋白得名于《星際旅行》系列中一種具有無限繁殖能力的毛蓬蓬的生物形象,，最先發(fā)現(xiàn)于果蠅中。“從未有過人類惡性腫瘤與Tribbles直接相關(guān)的報道,，”文章高級作者,、病理學(xué)副教授Warren S. Pear博士說，這是一種人類癌癥相關(guān)的新蛋白,，功能特異,，表達于造血干細胞會產(chǎn)生勢不可擋的后果。
三項實驗提示AML中存在Tribbles,。首先,，造血干細胞會表達Tribbles-2（Trib-2）的小鼠都會發(fā)展為AML。并且Trib-2抑制C/EBPa蛋白的活性,，C/EBPa蛋白是在AML患者中常見的發(fā)生突變的蛋白,；AML患者血液樣本中Tribbles表達量升高。所有實驗都提示Tribbles通過抑制C/EBPa蛋白的活性誘發(fā)AML,。研究結(jié)果見于上周《Cancer Cell》,。
AML是一種惡性瘤，起源于白細胞,，當(dāng)骨髓中的未成熟免疫細胞匱乏時AML發(fā)展,。AML患者體內(nèi)，白細胞無法控制的極度生長和聚集導(dǎo)致貧血,、血液中正常白細胞匱乏,。
賓州大學(xué)亞伯拉姆森家族癌癥研究所（Abramson Family Cancer Research Institute）研究人員Pear和文章第一作者Karen Keeshan等在研究Notch蛋白的分子伴侶時偶然發(fā)現(xiàn)了Tribbles蛋白。Notch蛋白是一種分子開關(guān),，在多種細胞核中激活基因轉(zhuǎn)錄,，并且依靠生化環(huán)境，開啟或者關(guān)閉特定途徑,。
Pear及其同事從果蠅實驗中了解到Tribbles蛋白與細胞生長,、細胞特化有關(guān)，并且與哺乳動物Tribbles基因關(guān)系密切,。實際上,，Tribbles得名原因在于，在果蠅中發(fā)生突變后會引起細胞無法控制地增殖,。
匯集其他研究小組的資料證實,，Tribbles蛋白功能如同一個支架，其募集的復(fù)合物能夠介導(dǎo)蛋白降解,。細胞發(fā)揮正常功能離不開蛋白降解,，Pear實驗室數(shù)據(jù)顯示Tribbles蛋白的基因發(fā)生錯誤會導(dǎo)致控制腫瘤的蛋白（比如腫瘤抑制物）發(fā)生降解，Pear 說：“我們現(xiàn)在所面臨的一個挑戰(zhàn)是白血病是由Tribbles引發(fā)那些蛋白降解導(dǎo)致的,。”
在小鼠中的這項發(fā)現(xiàn)在大量人類患者得到的數(shù)據(jù)中也成立,。一項調(diào)查AML患者基因表達的研究顯示,，C/EBPa發(fā)生缺陷的患者，Tribbles蛋白高表達,。
Keeshan說：“C/EBPa缺陷在肺癌等其它類型癌癥中也有出現(xiàn)過,，提示Trib2降解也可能出現(xiàn)于其它癌癥。另外,，將Trib2與人類癌癥聯(lián)系起來進一步支持了一種觀念：以蛋白降解物為靶標(biāo)將是治療惡性腫瘤的一個有效手段,。”
英文原文：
'Tribbles' Protein Implicated In Common And Aggressive Form Of Leukemia
Researchers at the University of Pennsylvania School of Medicine have identified a new protein associated with acute myelogenous leukemia (AML). Several lines of evidence point to a protein called Tribbles, named after the furry creatures that took over the starship Enterprise in the original Star Trek series. Tribbles was first described in fruit flies.
"Tribbles had never been directly linked to human malignancy," says senior author Warren S. Pear, MD, PhD, Associate Professor of Pathology and Laboratory Medicine. "This is a new protein to human cancer and has a specific and overwhelming effect when expressed in hematopoietic stem cells, the cell type that gives rise to all elements of the blood."
Three lines of evidence implicate Tribbles in AML. First, all mice engineered to express Tribbles-2 (Trib-2) in hematopoietic stem cells developed AML. They also found that Trib-2 inhibited C/EBP-, another protein that is frequently mutated in AML patients. Additionally, expression of the Tribbles protein was elevated in blood samples from AML patients, further suggesting that it contributes to AML. Overall, the findings suggest that Tribbles induces AML by inactivating the C/EBP- protein. The results were published in this week's issue of Cancer Cell.
AML is a malignancy that arises in white blood cells and develops when there is a defect in immature immune cells in the bone marrow. In AML, the uncontrolled, exaggerated growth and accumulation of white blood cells leads to anemia and a deficiency of normal white cells in the blood. AML is the most common type of leukemia in adults, with an estimated 10,100 new cases reported each year.
Pear, also a researcher in the Abramson Family Cancer Research Institute at Penn; first author and postdoctoral fellow Karen Keeshan, PhD; and colleagues found Tribbles by chance when looking for the molecular partners of another protein called Notch. Notch is a molecular switch of sorts, activating gene transcription in the nucleus of many types of cells, and depending on the biochemical context, turns certain pathways on and others off.
Pear and colleagues knew from fruit fly studies that the Tribbles protein was linked to cell growth and cell-fate determination and is closely related to the Tribbles gene in mammals. In fact, Tribbles is so named because, when mutated in flies, it causes cells to proliferate uncontrollably.
Accumulating evidence from several groups shows that Tribbles functions as a scaffold to bring together a complex that mediates protein degradation. Protein degradation is required for normal cellular function; however, data from the Pear lab suggests that mistakes in the expression of the Tribbles gene may lead to degradation of proteins that hold cancer in check, such as tumor suppressors. "One of our current challenges is to determine what other proteins Tribbles degrades to cause leukemia," says Pear.
The findings in mice were also validated in a large database of human cancer patients. In a survey of gene expression in AML patients, high Tribbles expression was found in a subset of patients who had been previously characterized by defects in C/EBP-.
According to Keeshan, "C/EBPa defects have also been identified in lung cancer and other tumors, suggesting the po
