《Nature》发现抑癌基因新功能 调控胚胎干细胞分化

【字体: 时间:2009年12月25日 来源:生物通

编辑推荐:

  生物通报道,俄亥俄州立大学免疫与遗传学系,分子遗传学系,癌症研究中心,英国Li Ka Shing中心,Beatson癌症研究所等处的科学家最近在Nature上发表了干细胞研究的最新成果。

  

生物通报道,俄亥俄州立大学免疫与遗传学系,分子遗传学系,癌症研究中心,英国Li Ka Shing中心,Beatson癌症研究所等处的科学家最近在Nature上发表了干细胞研究的最新成果。

 

在已经确认的哺乳动物细胞复制周期调控过程中,成视网膜母细胞瘤蛋白(retinoblastoma ProteinRb)具有限制细胞进入S期的功效。Rb蛋白通过与E2f1,E2f2E2f3结合并终止它们的活性来抑制细胞进入S期。

 

Rb基因是最早发现的肿瘤抑制基因,最初发现于儿童的视网膜母细胞瘤,因此称为Rb基因。在正常情况下,视网膜细胞含活性 Rb基因,控制着成视网膜细胞的生长发育以及视觉细胞的分化,当Rb基因一旦丧失功能或先天性缺失,视网膜细胞则出现异常增殖,肝成视网膜母细胞瘤。Rb基因失活还见于骨肉瘤。小细胞肺癌、乳腺癌等许多肿瘤,说明Rb基因的抑癌作用具有一定的广泛性。

 

Rb基因比较大,位于人13号染色体q14,含有27个外显子,转录4.7kbmRNA,编码蛋白质为P105,定位于核内,有磷酸化和非磷酸化两种形式,非磷酸化形式称活性型,能促进细胞分化,抑制细胞增殖。

 

研究小组选用一种独特转基因小鼠研究E2f蛋白对小鼠胚胎干细胞分化的调控影响。

 

研究发现,正常的祖细胞分化过程中,E2f1-3蛋白的主要功能是激活转录,这与现行的观点是不一致的,E2f1-3不是维持细胞分化的因子,而是保持细胞活性的因子。

 

在细胞分化过程中,E2f1-3具有复杂的调控作用,它通过与Rb蛋白结合抑制E2f靶标促使细胞退出细胞循环过程。失活的Rb蛋白在细胞分化过程中发挥一个控制E2f1-3蛋白活性的开关作用。

 

这项研究同样描述了这些蛋白如何在Rb突变的细胞中再次转变功能。这也许为多种癌症的治疗提供了新的视野。

(生物通 小茜)

生物通推荐原文检索

E2f13 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

 

Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine,

Department of Molecular Genetics, College of Biological Sciences,

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA

Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA

Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK

The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK

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

Department of Zoology, Miami University, Oxford, Ohio 45056, USA

These authors contributed equally to this work.

Present address: Division of Pediatric Hematology/Oncology, Childrens Hospital Boston; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Correspondence to: Gustavo Leone1,2,3 Correspondence and requests for materials should be addressed to G.L. (Email: Gustavo.Leone@osumc.edu).

 

Abstract

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 E2f13 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 E2f13 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 E2f13 from repressors to activators, leading to the superactivation of E2f responsive targets and ectopic cell divisions. Loss of E2f13 completely suppressed these phenotypes caused by Rb deficiency. This work contextualizes the activator versus repressor functions of E2f13 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles.

 

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