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J Cell Sci:雷帕霉素靶蛋白在癌症及再生医学中的重要作用

来源:生物谷 2012-03-21 22:06

左边的涡虫可以表达蛋白TOR,而右边的却不行;应用基因操作的方法可以破坏表达TOR蛋白的基因(Credit: Image courtesy of University of California, Merced)

近日,来自加利福尼亚大学的研究者表示,众所周知,扁虫有再生细胞的能力可以为我们治疗癌症以及再生医学如何更好地对疾病打靶提供很多理论依据,刊登在杂志Journal of Cell Science上的文章中,研究者指出了一种在人类和其它哺乳动物中所发现的一种由雷帕霉素靶蛋白质(TOR)所介导的信号通路,这种信号分子对于涡虫特有的组织再生至关重要,使该蛋白失活可以阻止涡虫再生,因此这就给我们了一个启示,如果在人类细胞中破坏此蛋白,便可以阻止癌细胞的增殖。

研究者Oviedo表示,这将给我们提供了一个模型,我们可以利用操作这个信号分子通路来学习干细胞的某些行为,另外研究者所发现的TOR蛋白(雷帕霉素靶蛋白)在癌症、衰老以及疾病恶化等疾病中扮演着重要的角色,但是具体作用机制并不清楚。Oviedo博士的实验室准备用涡虫(planaria)来研究解决相关问题,由于长时间科学界觉得涡虫并没有太高的科研价值,但是现在涡虫这种扁形虫却在理解干细胞的角色上至关重要,涡虫有自我组织修复的能力,这种能力却是空前的,而且这种修复可以帮助抵御癌症和退行性疾病,基于以上理论只是,研究者们破坏了涡虫中的TOR蛋白,并且将涡虫部分截肢,典型的情况下,涡虫可以进行自我修复。

但是在研究中,研究者发现涡虫自身所需的干细胞在正确的位置能够使组织再生长(regrow),但是不能使得重组重生(regenerate),也不能够替代已经在正常位置所形成的组织,这种再生的方式以前并未报道,另外,被破坏了TOR蛋白的涡虫并不能生长,尽管是在营养充足的情况下。为了阻止癌症蔓延,更好地理解TOR以及其扮演的角色可以有效地鼓励组织再生医学的发展以及更好的抵抗退行性疾病,比如阿尔兹海默病;研究生Harshani Peiris表示,涡虫可以让研究者更加清楚地看出自身整个机体内的反应,而不是单单在培养品中单个细胞的反应,我们目前对于涡虫机体内的各种反应在系统水平上有更前沿的见解。

(生物谷:T.Shen编译)

TOR Signaling Regulates Planarian Stem Cells and Controls Localized and Organismal Growth

T. Harshani Peiris, Frank Weckerle, Elyse Ozamoto, Daniel Ramirez, Devon Davidian, Marcos E. García-Ojeda and Néstor J. Oviedo*

The Target of Rapamycin (TOR) controls an evolutionarily conserved signaling pathway that modulates cellular growth and division by sensing levels of nutrients, energy and stress. As such, TOR signaling is a crucial component of tissues and organs that translates systemic signals into cellular behavior. The ubiquitous nature of TOR signaling, together with the difficulty to analyze tissue during cellular turnover and repair, have limited our understanding on how this kinase operates throughout the body. Here, we use the planarian model system to address TOR regulation at the organismal level. The planarian TOR homolog (Smed-TOR) is ubiquitously expressed, including stem cells (neoblasts) and differentiated tissues. Inhibition of TOR with RNA-interference severely restricts cell proliferation, allowing the study of neoblasts with restricted proliferative capacity during regeneration and systemic cell turnover. Strikingly, TOR signaling is required for neoblast response to amputation and localized growth (blastema). However, in the absence of TOR signaling, regeneration takes place only within differentiated tissues. In addition, TOR is essential to maintain the balance between cell division and cell death and its dysfunction leads to tissue degeneration and lack of organismal growth in the presence of nutrients. Finally, TOR function is likely mediated through TOR Complex 1 as its disruption recapitulates signs of TOR-phenotype. Our data reveal novel roles for TOR signaling in controlling adult stem cells at a systemic level and suggest a new paradigm to study TOR function during physiological turnover and regeneration.

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