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E2fs可激活干细胞分化
分类:国际医学技术 来源:本站编辑部 作者:med00 职称:
摘要:
如果我们可以抑制癌细胞中的这些蛋白,或许就能预防肿瘤生长,而且不会对正常细胞产生很大的影响。

一项新的研究关于干细胞生长和分化关键步骤的发生,以及该步骤的逆转导致癌症的机制。研究人员表示,有3个主要的蛋白,它们首先会激活干细胞增殖,然后随着细胞分化成最终的类型,这些蛋白会改变功能,使得细胞不在分裂。因此这些蛋白或能为许多癌症提供一个安全新颖的治疗靶标。

在正在发育的动物中,干细胞会增殖和分化形成生命所需要的器官。这项新的研究表明,在这个过程中,某一关键的步骤的发生,以及该过程的逆转导致癌症的机制。

研究人员表示,有三种蛋白在干细胞转变成最终类型过程中承担了重要的角色。这三种蛋白分别叫E2f1,E2f2和E2f3。

这些蛋白能够刺激干细胞生长和分化。但是一旦干细胞开始分化成最终的细胞类型-比如视网膜细胞或肠细胞,这3种蛋白会转变功能使干细胞不再分裂。这项研究同样描述了这些蛋白如何在眼癌基因(retinoblastoma,Rb)突变的细胞中再次转变功能。Rb基因变异存在于在许多的癌症中,这表明,这些蛋白可能提供一个安全新颖的治疗靶标定位这些肿瘤。

这项研究结果发布在12月17日的Nature上。研究人员表示,这些E2fs是干细胞的基因激活因子,但另一方面当干细胞开始分化时它们会转变成基因抑制因子。

这是细胞分化过程中很重要的一步。在器官形成过程中,由于只需要固定数量的细胞,所以需要在分化的过程中进行抑制。蛋白质这种从激活因子到抑制因子的改变是停止细胞继续增殖必需的。在这之前,科学家认为,这些蛋白对分化的细胞具有重要作用,但只是在增殖的细胞中起作用,比如干细胞,其实这是不正确的。

原始出处:

Nature 462, 930-934 (17 December 2009) | doi:10.1038/nature08677

E2f1–3 switch from activators in progenitor cells to repressors in differentiating cells

Jean-Leon Chong1,2,3,9, Pamela L. Wenzel1,2,3,9,10, M. Teresa Sáenz-Robles4,9, Vivek Nair1,2,3, Antoney Ferrey1,2,3, John P. Hagan1,3, Yorman M. Gomez1,2,3, Nidhi Sharma1,2,3, Hui-Zi Chen1,2,3, Madhu Ouseph1,2,3, Shu-Huei Wang1,2,3, Prashant Trikha1,2,3, Brian Culp1,2,3, Louise Mezache1,2,3, Douglas J. Winton5, Owen J. Sansom6, Danian Chen7, Rod Bremner7, Paul G. Cantalupo4, Michael L. Robinson8, James M. Pipas4 & Gustavo Leone1,2,3

1 Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine,
2 Department of Molecular Genetics, College of Biological Sciences,
3 Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA
4 Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
5 Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK
6 The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK
7 Toronto Western Research Institute, University Health Network, Departments of Ophthalmology and Visual Science, and Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5T 2S8, Canada
8 Department of Zoology, Miami University, Oxford, Ohio 45056, USA
9 These authors contributed equally to this work.
10 Present address: Division of Pediatric Hematology/Oncology, Children’s Hospital Boston; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
11 Correspondence to: Gustavo Leone1,2,3 Correspondence and requests for materials should be addressed to G.L.

In the established model of mammalian cell cycle control, the retinoblastoma protein (Rb) functions to restrict cells from entering S phase by binding and sequestering E2f activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase1, 2. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examined the effects of E2f1, E2f2 and E2f3 triple deficiency in murine embryonic stem cells, embryos and small intestines. We show that in normal dividing progenitor cells E2f1–3 function as transcriptional activators, but contrary to the current view, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells E2f1–3 function in a complex with Rb as repressors to silence E2f targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2f1–3 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f1–3 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f1–3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.

 

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浏览次数:5338次   发布日期:2009-12-24

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