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一种白血病相关蛋白——Tribbles

来源:生物通 2006-11-21 08:35

最近宾州大学医学院研究人员鉴定出一种急性髓系白血病(acute myelogenous leukemia ,AML)相关蛋白——Tribbles。

Tribbles蛋白得名于《星际旅行》系列中一种具有无限繁殖能力的毛蓬蓬的生物形象,最先发现于果蝇中。“从未有过人类恶性肿瘤与Tribbles直接相关的报道,”文章高级作者、病理学副教授Warren S. Pear博士说,这是一种人类癌症相关的新蛋白,功能特异,表达于造血干细胞会产生势不可挡的后果。

三项实验提示AML中存在Tribbles。首先,造血干细胞会表达Tribbles-2(Trib-2)的小鼠都会发展为AML。并且Trib-2抑制C/EBPa蛋白的活性,C/EBPa蛋白是在AML患者中常见的发生突变的蛋白;AML患者血液样本中Tribbles表达量升高。所有实验都提示Tribbles通过抑制C/EBPa蛋白的活性诱发AML。研究结果见于上周《Cancer Cell》。

AML是一种恶性瘤,起源于白细胞,当骨髓中的未成熟免疫细胞匮乏时AML发展。AML患者体内,白细胞无法控制的极度生长和聚集导致贫血、血液中正常白细胞匮乏。

宾州大学亚伯拉姆森家族癌症研究所(Abramson Family Cancer Research Institute)研究人员Pear和文章第一作者Karen Keeshan等在研究Notch蛋白的分子伴侣时偶然发现了Tribbles蛋白。Notch蛋白是一种分子开关,在多种细胞核中激活基因转录,并且依靠生化环境,开启或者关闭特定途径。

Pear及其同事从果蝇实验中了解到Tribbles蛋白与细胞生长、细胞特化有关,并且与哺乳动物Tribbles基因关系密切。实际上,Tribbles得名原因在于,在果蝇中发生突变后会引起细胞无法控制地增殖。

汇集其他研究小组的资料证实,Tribbles蛋白功能如同一个支架,其募集的复合物能够介导蛋白降解。细胞发挥正常功能离不开蛋白降解,Pear实验室数据显示Tribbles蛋白的基因发生错误会导致控制肿瘤的蛋白(比如肿瘤抑制物)发生降解,Pear 说:“我们现在所面临的一个挑战是白血病是由Tribbles引发那些蛋白降解导致的。”

在小鼠中的这项发现在大量人类患者得到的数据中也成立。一项调查AML患者基因表达的研究显示,C/EBPa发生缺陷的患者,Tribbles蛋白高表达。

Keeshan说:“C/EBPa缺陷在肺癌等其它类型癌症中也有出现过,提示Trib2降解也可能出现于其它癌症。另外,将Trib2与人类癌症联系起来进一步支持了一种观念:以蛋白降解物为靶标将是治疗恶性肿瘤的一个有效手段。”

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 possibility that Trib2 dysregulation may be identified in other tumors. Furthermore, linking Trib2 to human cancer adds further support to the notion that targeting the protein degradation machinery will be a useful strategy in treating malignancy."

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