TGF—β的结构,受体及信号转导

转化生长因子β（ＴＧＦ－β）是一种多功能细胞因子。人、鼠等哺乳动物的ＴＧＦ－β已克隆出β１、β２、β３３种亚单位。活性ＴＧＦ－β是分子量的２５ｋＤ的同源二聚体,每个单体由１１２个氨基酸组成。ＴＧＦ－β受体有ＴβＲⅠ￣Ⅴ、Ｅｎｄｏｇｌｉｎ等。其中ＴβＲⅠ、ＴβＲⅡ属丝氨酸／苏氨酸激酶家族,在ＴＧＦ－β信号转导中起主导作用。ＴＧＦ－β与ＴβＲⅡ结合后,再结合ＴβＲⅠ,然后ＴβＲⅡ磷酸化ＴβＲⅠ,后作     

TGF—β与细胞周期调节

作为一类重要的生长负调节因子;TGF－β能够抑制多种类型细胞的生长,并将其阻断在GI期。TGF－β对细胞周期的调节作用是通过：（1）下调细胞周期驱动器如cyclin、cdk等的表达水平;（2）降低G1期cyclin／cdk复合物的活性;（3）调节p27、p21和p15等cdk抑制因子的表达及活性等。此外,一些原癌基因和肿瘤抑制基因的产物如c－myc、RB等也在这一过程中起着重要作用。     

TGF—β与移植免疫

转化生长因子－β(transforming growth facter-β,TGF－β）是一种对细胞的生长、分化和免疫功能都有重要调节作用的多肽。在器官移植中TGF－β主要是一种负的免疫调节剂。本综述简要介绍了TGF－β与器官移植免疫排斥反应的关系。     

TGFβ信号通路与肿瘤

TGFβ影响细胞的增殖和分化，在肿瘤发生与进展、细胞外基质形成和免疫调节等过程中发挥重要作用。TGFβ通过脑膜上的受体和胞内Smads家族向核内传递信号，调控靶基因。肿瘤中的TGFβ信号通路异常有其多样性和复杂性。近年来，TGFβ信号通路的研究取得了突破性进展，本文综述了恶性肿瘤中的TGFβ信号通路的异常。     

Conditional overexpression of TGFβ1 promotes pulmonary inflammation,apoptosis and mortality via TGFβR2 in the developing mouse lung

Background

Earlier studies have reported that transforming growth factor beta 1(TGFβ1) is a critical mediator of hyperoxia-induced acute lung injury (HALI) in developing lungs, leading to impaired alveolarization and a pulmonary phenotype of bronchopulmonary dysplasia (BPD). However, the mechanisms responsible for the TGFβ1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFβ1 signaling via TGFβR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI.

Methods

We utilized lung epithelial cell-specific TGFβ1 overexpressing transgenic and TGFβR2 null mutant mice to evaluate the effects on neonatal mortality as well as pulmonary inflammation and apoptosis in developing lungs. Lung morphometry was performed to determine the impaired alveolarization and multicolor flow cytometry studies were performed to detect inflammatory macrophages and monocytes in lungs. Apoptotic cell death was measured with TUNEL assay, immunohistochemistry and western blotting and protein expression of angiogenic mediators were also analyzed.

Results

Our data reveals that increased TGFβ1 expression in newborn mice lungs leads to increased mortality, macrophage and immature monocyte infiltration, apoptotic cell death specifically in Type II alveolar epithelial cells (AECs), impaired alveolarization, and dysregulated angiogenic molecular markers.

Conclusions

Our study has demonstrated the potential role of inhibition of TGFβ1 signaling via TGFβR2 for improved survival, reduced inflammation and apoptosis that may provide insights for the development of potential therapeutic strategies targeted against HALI and BPD.     

TGF—β的信号转导的调控

TGF－β家族通过调节靶基因的表达发挥作用,其细胞内信号转导通路是TGF－β的膜受体与靶基因之间的桥梁。TGF－β信号转导的调控是多层次、多水平的。凡能够调控以上信号转导过程中蛋白质－蛋白质和蛋白质－DNA相互作用的因子就能在各个环节上影响TGF－β家族的信号转导,从而产生多种多样的生物学效应。     

TGF－β家族及其受体组成

ＴＧＦ－β家族及其受体组成ＴｈｅＴＧＦ－βｆａｍｉｌｙａｎｄｉｔｓｃｏｍｐｏｓｉｔｅｒｅｃｅｐｔｏｒｓＪｏａｎ　Ｍａｓｓａｇｕｅ,ＬｉｌｉａｎａＡｔｔｉｓａｎｏａｎｄＪｅｆｆｒｅｙＬＷｒａｎａ￥／／张德胜译,曹惠婷校阅（中国科学院上海生物化学研究所２...     

TGF—β家族的细胞信号转导

转化生长因子β（ＴＧＦ－β）家族成员与各自的膜受体结合后,使通路限制性（ｐａｔｈｗａｙ－ｒｅｓｔｒｉｃｔｅｄ）ＳＭＡＤｓ磷酸化,后者再与Ｓｍａｄ４形成杂聚体并转位至细胞核,调节一些基因的转录而产生生物学效应。抑制性ＳＭＡＤｓ可阻断通路限制性ＳＭＡＤｓ的磷酸化。     

转化生长因子—β（TGF—β）的结构

1978年,Delarco和Todar首先发现病毒转化的细胞能分泌一种具有使正常大鼠肾成纤维细胞表型发生转化能力的因子,它在表皮生长因子(EGF)存在的情况下使贴壁生长的细胞特性发生改变,获得在软琼脂培养基上生长形成克隆的能力,并失去生长密度依赖的抑制作用。因此,这种细胞因子被命名为转化生长因子-β(TGF-β)。在过去的10年中,发现TGF-β实际上是一种具有多种生物学功能的细胞因     

TGF—β超家族信号传导机制研究进展

ＴＧＦ－β超家族由一大类具有共同生物学特性的细胞因子所组成,在生长控制、物质代谢等方面均有极其重要的作用。它们与Ⅱ型受体和Ⅰ型受体形成异在聚体复合物后激活Ⅰ型受体,然后通过被称为ＳＭＡＤ蛋白的信号蛋白,将信号从细胞浆转导到细胞核中。     

TGF—β在前列腺癌骨转移中的研究进展

进展期前列腺癌多会发生骨转移,导致患者骨质破坏甚至死亡。前列腺癌发生骨转移的机制目前尚未研究清楚。既往多认为是因为前列腺癌细胞表面携带者容易在骨环境中生长的表型。但是目前多认为是肿瘤细胞与骨骼微环境之间的相互作用导致的结果。它们之间是通过细胞因子来传递信息。在众多因子中,TGF-β对前列腺癌骨转移灶中的各种细胞都起着重要作用。研究表明在体外实验中TGF-β的作用极易受到细胞生长环境的影响,表现出不同的功能。这提示着TGF-β信号通路和其他信号通路之间存在非常强的交互作用。本文的重点在于对TGF-β在前列腺癌骨转移中的作用研究进展进行综述,阐述TGF-β对转移灶中不同细胞的作用．为今后肿瘤的治疗研究寻找一个好的方向。     

阻碍TGFβ信号传递的新型蛋白

美国Millennium Pharmaceuticals公司8月19日宣布,使用该公司独立开发的基因表达分析技术RADE,表达了阻碍转化生长因子β(TGFβ)的信号传递的新型蛋白.有关这种蛋白的论文刊登在The Proceedings of the National Academy of Sciences杂志上.     

Pyrazolone based TGFβR1 kinase inhibitors

Interruption of TGFβ signaling through inhibition of the TGFβR1 kinase domain may prove to have beneficial effect in both fibrotic and oncological diseases. Herein we describe the SAR of a novel series of TGFβR1 kinase inhibitors containing a pyrazolone core. Most TGFβR1 kinase inhibitors described to date contain a core five-membered ring bearing N as H-bond acceptor. Described herein is a novel strategy to replace the core structure with pyrazolone ring, in which the carbonyl group is designed as an H-bond acceptor to interact with catalytic Lys 232.     

脾切除对肝纤维化大鼠肝脏TGFβ1 的表达和血清TGFβ1 水平的影响

目的:研究脾切除对肝纤维化大鼠肝脏TGFβ1的表达和血清TGFβ1 水平的影响,探讨脾切除在肝纤维化中的意义.方法:用CCL,建立50例肝纤维化大鼠模型.于建模第3周,6周,及8周分别取大鼠肝脏和脾脏标本.用免疫组化SP 方法测定其TGFβ1 的表达,HE和姬姆萨染色检测肝纤维化.应用双抗体夹心ELISA 方法测定15 例模型大鼠行脾脏切除前后的血清TGFβ1 水平,以及15 例对照组大鼠的血清TGFβ1 水平,并于术后4周取两组大鼠的肝脏标本,用免疫组化sP 方法测定其TGFβ1的表达.应用CMIAS8 彩色图像系统对阳性目标进行分析和处理.结果:随着肝纤维化程度的进展,大鼠肝脏和脾脏TGFβ1的表达也随之增加(P<0.01).脾切除组大鼠其血清 TGF-β1 的水平显著低于对照组大鼠(P<0.05),且脾切除组大鼠肝脏TGFβ1 的表达低于对照组大鼠(P<0.05).结论:脾切除术在一定程度上可延缓肝纤维化的发展.     

RanBPM interacts with TβRI,TRAF6 and curbs TGF induced nuclear accumulation of TβRI

Transforming growth factor β (TGF-β), a cytokine, and its receptors play a vital role during normal embryogenesis, cell proliferation, differentiation, apoptosis and migration. Ran-binding protein in the microtubule-organizing center (RanBPM) serves as a scaffold protein that has been shown to interact with many other proteins, such as MET, Axl/Sky, TRAF6, IFNR, TrKA and TrkB in addition to p75NTR. In the current study, we have identified RanBPM as a novel binding partner of TβRI by yeast two-hybrid assay. The TβRI and RanBPM association was confirmed by co-immunoprecipitation and GST pull-down experiments. Additionally, expression of RanBPM abrogated the interaction between TβRI and TRAF6. Furthermore, RanBPM could depress TGF-β induced TRAF6 ubiquitination, subsequent NF-κB signaling pathway, and block TGF-β induced TβRI nuclear accumulation. Taken together, our results reveal that RanBPM may modulate TGF-β-mediated downstream signaling and biological functions.     

Effects of growth factors FGF4, TGFα, and TGFβ1 on development of parthenogenetic embryos of C57BL/6 mice

We studied the effects of three growth factors, fibroblast growth factor (FGF4), transforming growth factor (TGF), and transforming growth factor 1 (TGF1), on development of diploid parthenogenetic embryos of C57BL/6 mice, which are not capable of developing to somatic stages. Parthenogenetic embryos were treated with growth factors at optimal doses in vitro at the morula-blastocyst stages and transplanted in the uterus of pseudopregnant females. FGF4 and TGF improved the development of parthenogenetic embryos at the preimplantation stages and the number of blastocysts increased under the influence of TGF. All three growth factors improved the implantation of embryos in the uterus. When FGF4 or TGF1 2.4 were added to the nutrient medium, 2.4 or 1.6%, respectively, of parthenogenetic embryos reached the somatic stages in utero. No somitic embryos were observed in the control. The treatment of parthenogenetic embryos with two growth factors, FGF4 and TGF1 , simultaneously increased the amount of somatic embryos to 7.5%, while combination of three growth factors in creased the amount of such embryos to 16.7%. In the latter case, some parthenogenetic embryos reached the stage of 25–27 pairs of somites and were 2.0–2.5 mm long. The data we obtained suggest that, when combined, the growth factors FGF4, TGF, and TGF1 possessed a synergistic effect leading to a significant improvement of the development of parthenogenetic C57BL/6 embryos.__________Translated from Ontogenez, Vol. 36, No. 2, 2005, pp. 145–150.Original Russian Text Copyright © 2005 by Penkov, Platonov, Dimitrov, Mironova, Konyukhov.     

SMAD介导的TGF—β信号转导与大肠癌

转化生长因子β（TGF－β）家族成员与各自的膜受体（Ⅰ型及Ⅱ型受体）结合后,通路限制性SMADs被磷酸化,并与共介导Smad4形成杂聚体而转位至细胞核,从而调节一些靶基因的转录而对TGF－β产生反应,抑制性SMADs对此过程有负性调节作用,由SMADs介导的TGF－β信号转导通路的异常在大肠癌的发生发展中发挥重要作用,主要包括膜受体,通路限制性SMADs和共介导Smad4的改变,而抑制SMADs的改变甚为少见。