转化生长因子β及其生物学效应

转化生长因子β（ＴＧＦβ）属于一处多功能多肽家族,在免疫抑制、抗炎症反应、对增殖和细胞间质产生的调控、损伤修复等方面起重要作用。ＴＧＦβ表达和信号转导失常与多处疾病的发生有关。     

转化生长因子β1与老年性痴呆

老年性痴呆 (简称ＡＤ)是一种渐进性大脑退行性变性病 ,其发病率随年龄增长而显著升高 ,6 5～ 80岁人群约为 5 % ,80岁以上者可达 2 0 %。我国 6 0岁以上的人口已近1 .3亿 ,ＡＤ即将成为医学和社会面临的严峻问题 ,已引起政府和医学工作者的关注。对ＡＤ的研究在美国、欧州和日本倍受重视 ,并取得了一定成果[1] 。β 淀粉样蛋白 (Ａβ)在中枢神经系统中的沉积是ＡＤ的一个标志 ,并可能是神经退收稿日期 :2 0 0 0 0 5 11作者简介 :吴晓英 ( 196 1— ) ,女 ,硕士 ,讲师。化的一个原因[2 ] 。在脑对损伤的反应中 ,转化生长因子 β1 (ＴＧＦ …     

转化生长因子-β族信号的转导

ＴＧＦ－β族细胞因子通过各自信号转导产生多种生物学效应,其基本过程是：信号沿ＴＧＦ－β族配体→受体→ＳＭＡＤ蛋白→转录因子→ＤＮＡ表达的次序较导,在ＴＧＦ－β族各因子刺激各自具有蛋白激酶活性的两型膜受体时,各因子先结合Ⅱ型受体,结合配体的Ⅱ型受体再激活Ⅰ型受体。活化的Ⅰ型受体磷酸化通路特异性ＳＭＡＤ,后者与公用性ＳＭＡＤ结合后从胞浆移至核内,核内ＳＭＡＤ通过与转录因子结合和直接与ＤＮＡ结合调节基因     

转化生长因子—β对细胞外基质基因表达调节作用的研究进展

转化生长因子－β是一类具有激素样活性的多肽生长因子,许多正常和转化细胞均可合成并分泌ＴＧＦ－β,ＴＧＦ－β既可刺激细胞的增殖,又可刺激细胞的分化,对细胞进行双向调节。细胞外基质对细胞的增殖和分化也具有控制作用,ＥＣＭ主要成份的ｍＲＮＡ表达可被ＴＧＦ－β诱导和调节,而且两者具有一定的相关性。提示ＴＧＦ－β可能是通过ＥＣＭ实现其对细胞的双向调节。     

转化生长因子β的细胞生物学

无限繁殖是肿瘤细胞区别于正常细胞的主要特征之一。近年来,人们对细胞的生长分化及其调控机制的认识已有了深刻的变化。正常细胞均存在促进(如TGFα)和抑制(如TGFβ)其生长的多肽生长因子,该两种因子的平衡决定着细胞生长的生理或病理性变化。本文将简述转化生长因子β(TGFβ)近年来研究的一些进展。一、TGFβ是一组具有调节功能的多肽目前,已发现的TGFβ有五种亚型:TGFβ_1-TGFβ_5,其氨基酸有95-80%的同源性。TGFβ_1-TGFβ_3,其编码基因分别位于第19、1和14染色体上。TGFβ_1     

转化生长因子β的受体

转化生长因子β的受体冯起宇（北京大学生命科学学院,北京１００８７１）关键词ＴＧＦ－β,受体转化生长因子β（ＴＧＦ－β）是２５ｋ的多肽,它是一种多功能的细胞因子,广泛影响细胞的增殖、分化、胞外基质中产物的生成等一系列生命过程［１］。ＴＧＦ－β对细胞的影...     

转化生长因子β在细胞凋亡抗调亡中的作用机制

转化生长因子β(TGF-β)在生物发育、组织形成与更新、伤口的愈合、细胞增殖、迁移与免疫反应中起着重要的调节作用.TGF-β既能诱导某些类型细胞的凋亡反应,又能增强某些类型细胞的生存力,具有一定的抗细胞凋亡作用.TGF-β生物效应的这种显而易见的矛盾性质并不仅仅存在于细胞的生死和存活的凋节过程中,还可见于TGF-β介导的其他细胞效应中.因此,TGF-β介导的广泛和对立的生物效应的机制成为人们关注和研究的焦点,最近几年人们已开始逐渐认识和了解对TGF-β诱导细胞凋亡和抗细胞凋亡的机制.在此,我们仅就某些研究进展作一简单的介绍.     

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     

转化生长因子β受体的研究进展

转化生长因子β受体为胞膜蛋白,存在5种形态,Ⅲ型受体主要是调节受体与配体之间的亲和力及Ⅱ型受体的膜上表达.功能性受体则主要为Ⅰ、Ⅱ型.Ⅰ、Ⅱ型受体在介导信号传递时相互配合,又存在分工不同：Ⅰ型受体为介导转化生长因子β促细胞外基质合成的信号通道.而Ⅱ型受体则与细胞的增殖、分化密切相关.     

Transforming growth factor (TGF)-alpha in human milk

Transforming growth factor (TGF)-alpha and epidermal growth factor (EGF) were measured in human milk by means of homologous radioimmunoassay. As previously reported, EGF concentration in the colostrum was approximately 200 ng/ml and decreased to 50 ng/ml by day 7 postpartum. The value of immunoreactive (IR)-TGF-alpha was 2.2-7.2 ng/ml, much lower than that of EGF. In contrast to EGF, the concentration of IR-TGF-alpha was fairly stable during the 7 postpartum days. There was no relationship between the concentrations of IR-TGF-alpha and IR-EGF, suggesting that the regulatory mechanism in the release of the two growth factors is different. On gel-chromatography using a Sephadex G-50 column, IR-EGF appeared in the fraction corresponding to that of authentic human EGF, while 70%-80% of the IR-TGF-alpha was eluted as a species with a molecular weight greater than that of authentic human TGF-alpha. Although the physiological role of TGF-alpha in milk is not known, it is possible that it is involved in the development of the mammary gland and/or the growth of newborn infants.     

Ursolic acid, an antagonist for transforming growth factor (TGF)-beta1

Transforming growth factor-beta (TGF-beta), a multifunctional cytokine which is involved in extracellular matrix modulation, has a major role in the pathogenesis and progression of fibrotic diseases. We now report the effects of ursolic acid on TGF-beta1 receptor binding and TGF-beta1-induced cellular functions in vitro. Ursolic acid inhibited [(125)I]-TGF-beta1 receptor binding to Balb/c 3T3 mouse fibroblasts with an IC(50) value of 6.9+/-0.8 microM. Ursolic acid dose-dependently recovered reduced proliferation of Minc Mv1Lu cells in the presence of 5 nM of TGF-beta1 and attenuated TGF-beta1-induced collagen synthesis and production in human fibroblasts. Molecular dynamics simulations suggest that ursolic acid may interact with the hydrophobic region of the dimeric interface and thereby inhibit the binding of TGF-beta1 to its receptor. All these findings taken together show that ursolic acid functions as an antagonist for TGF-beta1. This is the first report to show that a small molecule can inhibit TGF-beta1 receptor binding and influence functions of TGF-beta1.     

Suppression of latent transforming growth factor (TGF)-beta1 restores growth inhibitory TGF-beta signaling through microRNAs

Cancer cells secreting excess latent TGF-β are often resistant to TGF-β induced growth inhibition. We observed that RNAi against TGF-β1 led to apoptotic death in such cell lines with features that were, paradoxically, reminiscent of TGF-β signaling activity and that included transiently enhanced SMAD2 and AKT phosphorylation. A comprehensive search in Hela cells for potential microRNA drivers of this mechanism revealed that RNAi against TGF-β1 led to induction of pro-apoptotic miR-34a and to a globally decreased oncomir expression. The reduced levels of the oncomirs miR-18a and miR-24 accounted for the observed derepression of two TGF-β1 processing factors, thrombospondin-1, and furin, respectively. Our data suggest a novel mechanism in which latent TGF-β1, thrombospondin 1, and furin form a microRNA-mediated regulatory feedback loop. For cells with high levels of latent TGF-β, this provides a potentially widespread mechanism of escape from TGF-β-mediated growth arrest at the earliest point in the signaling pathway, TGF-β processing.     

Transforming growth factor (TGF)-beta1 stimulates pulmonary fibrosis and inflammation via a Bax-dependent, bid-activated pathway that involves matrix metalloproteinase-12

Fibrosis, apoptosis, and the exaggerated production of transforming growth factor (TGF)-beta(1) are juxtaposed in a variety of pulmonary diseases including the interstitial lung diseases and asthma. In these disorders, the relationships between these responses are not well defined. In addition, the apoptosis pathways that contribute to these responses and the mechanism(s) of their contribution have not been described. We hypothesized that BH3 domain-only protein-induced apoptosis plays an important role in the pathogenesis of TGF-beta(1)-induced pulmonary responses. To test this hypothesis, we characterized the effects of transgenic TGF-beta(1) in mice with wild type (WT) and null Bax loci. To investigate the mechanisms of Bax activation and its effector functions, we also compared the effects of TGF-beta(1) in mice with WT and null Bid and matrix metalloproteinase (MMP)-12 loci, respectively. These studies demonstrate that TGF-beta(1) is a potent stimulator of Bax, Bid, and MMP-12. The studies also demonstrate that Bax and Bid play key roles in the pathogenesis of TGF-beta(1)-induced inflammation, fibrosis, and apoptosis; that TGF-beta(1) stimulates MMP-12, TIMP-1, and cathepsins and inhibits MMP-9 and p21 via Bax- and Bid-dependent mechanisms; and that TGF-beta(1)-stimulated pulmonary fibrosis is ameliorated in MMP-12-deficient animals. Finally, they demonstrate that Bax, Bid, and MMP-12 play similar roles in bleomycin-induced fibrosis, thereby highlighting the importance of this Bid-activated, Bax-mediated pathway and downstream MMP-12 in a variety of fibrogenic settings.     

Transforming growth factor-beta(1), -beta(2), -beta(3), basic fibroblast growth factor and vascular endothelial growth factor expression in keratinocytes of burn scars

Keratinocytes are increasingly recognized as key regulators of skin inflammation and remodeling, as they are capable of producing growth factors and cytokines that are important mediators in the wound healing process. We investigated the expression and distribution of TGF-beta 1 mRNA by mRNA in situ hybridization and of TGF-beta 1, TGF-beta 2, TGF-beta 3, bFGF and VEGF protein expression using immunohistochemistry in spontaneously healed, partial-thickness burns and compared this with the expression of these markers in matched unburned skin. This was done to assess their role in the remodeling phase of burn wound healing. Punch biopsies were taken from both partial-thickness burns after re-epithelialization and from matched, unburned skin. At 4 and 7 months post-burn, biopsies were taken of normotrophic and hypertrophic scars that had developed in these wounds. We observed a higher expression of all mentioned growth factors in keratinocytes in scars at 1 month post-burn compared with matched unburned skin. At 4 months, keratinocytes still displayed a higher expression of TGF-beta 3 and bFGF, but the expression of TGF-beta 1, TGF-beta 2 and VEGF was normalized. The expression of TGF-beta 3 in the epidermis of hypertrophic scars was slightly higher than in normotrophic scars. At 7 months post-burn, all growth factors studied showed a normal expression on keratinocytes. Our results suggest that keratinocytes are not only involved in re-epithelialization, but also in the scar maturation. The data support the idea that keratinocytes not only respond to cytokines and growth factors in an autocrine fashion, but also exert regulatory paracrine effects on contiguous cells.     

Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling

Transforming growth factor (TGF)-beta1 is a key cytokine involved in the pathogenesis of fibrosis in many organs, whereas interleukin (IL)-6 plays an important role in the regulation of inflammation. Recent reports demonstrate interaction between the two cytokines in disease states. We have assessed the effect of IL-6 on TGF-beta1 signaling and defined the mechanism by which this occurred. Stimulation of Smad-responsive promoter (SBE)4-Lux activity by TGF-beta1 was significantly greater in the presence of IL-6 than that induced by TGF-beta1 alone. Augmented TGF-beta1 signaling following the addition of IL-6 appeared to be mediated through binding to the cognate IL-6 receptor, the presence of which was confirmed by fluorescence-activated cell sorting and Stat-specific signaling. TGF-beta1 receptors internalize by both caveolin-1 (Cav-1) lipid raft and early endosome antigen 1 (EEA-1) non-lipid raft pathways, with non-lipid raft-associated internalization increasing TGF-beta1 signaling. Affinity labeling of TGF-beta1 receptors demonstrated that IL-6 stimulation resulted in increased partitioning of TGF-beta receptors to the non-lipid raft fraction. There was no change in expression of Cav-1; however, following IL-6 stimulation, co-immunoprecipitation demonstrated decreased association of IL-6 receptor with Cav-1. Increased TGF-beta1-dependent Smad signaling by IL-6 was significantly attenuated by inhibition of clathrin-mediated endocytosis and augmented by depletion of membrane cholesterol. These results indicate that IL-6 increased trafficking of TGF-beta1 receptors to non-lipid raft-associated pools results in augmented TGF-beta1 Smad signaling.     

Transforming growth factor (TGF beta) decreases the proliferation of human bone marrow fibroblasts by inhibiting the platelet-derived growth factor (PDGF) binding

Human bone marrow fibroblasts were cultivated and characterized by immunofluorescent staining and electron microscopy. Their interactions with PDGF and TGF beta were studied. While a positive intracellular antifibronectin staining was observed, the cultured cells were not labeled with specific antibodies toward factor VIII von Willebrand factor (F VIII/vWF), desmin, and macrophage antigen. Moreover, electron microscopy excluded the presence of endothelial cells by the absence of Weibel-Palade bodies. The binding of pure human PDGF to the cultured bone marrow fibroblasts was investigated. Addition of an excess of unlabeled PDGF decreased the binding to 75 and 80%, which means that the nonspecific binding represented 20-25% of total binding, whereas epidermal growth factor (EGF) had no effect. Two classes of sites were detected by Scatchard analysis with respectively 21,000 and 37,000 sites per cell, with a KD of 0.3 x 10(-10) M and KD of 0.5 x 10(-9) M. The stimulation of DNA synthesis by PDGF was quantified by [3H]thymidine incorporation. When PDGF was added alone at a concentration of 15 ng/ml, it induced a maximal DNA synthesis of 400%, which increased up to 900%, in the presence of platelet-poor plasma (PPP). On the other hand, PDGF-induced fibroblast proliferation was inhibited in a dose-dependent manner by TGF beta. This inhibition was related to a significantly decreased binding of 125I-labeled PDGF observed in the presence of TGF beta. Our results suggested that PDGF and TGF beta could modulate the growth of bone marrow fibroblasts.     

Transforming growth factor-beta (TGF beta) inhibits TGF alpha expression in bovine anterior pituitary-derived cells.

Transforming growth factor-beta 1 (TGF beta 1) is a multifunctional regulator of cell growth and differentiation. We report here that TGF beta 1 decreased the proliferation of nontransformed bovine anterior pituitary-derived cells grown in culture. We have previously demonstrated that these cells express both TGF alpha and its receptor [the epidermal growth factor (EGF) receptor] and that expression can be stimulated by phorbol ester (TPA) and EGF. TGF beta 1 treatment over a 2-day period decreased the proliferation of pituitary cells. This decreased growth rate was accompanied by a decrease in the TGF alpha mRNA level. The effect of TGF beta 1 on TGF alpha mRNA down-regulation was both dose dependent (maximal effect observed at 1.0 ng/ml TGF beta 1) and time dependent (minimum of 2-day treatment with TGF beta 1 was required before a decrease in TGF alpha mRNA was observed). Studies on TGF alpha mRNA stability indicated that TGF beta 1 did not alter the TGF alpha mRNA half-life. Treatment of the TGF beta 1 down-regulated cells with EGF resulted in the stimulation of TGF alpha mRNA levels; thus, the TGF beta 1-treated cells remained responsive to EGF. The decreased proliferation in response to TGF beta 1 could be only partially reversed by simultaneous treatment of the cells with EGF (10(-9)M) and TGF beta 1 (3.0 ng/ml). Qualitatively, the TGF beta 1-induced reduction of TGF alpha mRNA content was independent of cell density. TGF beta 1 treatment of the anterior pituitary-derived cells also reduced the levels of c-myc and EGF receptor mRNA. These results represent the first demonstration of the down-regulation of TGF alpha synthesis by a polypeptide growth factor and suggest that TGF beta 1 may be a physiological regulator of TGF alpha production in vivo.     

Transforming growth factor (TGF)-beta 1 internalization: modulation by ligand interaction with TGF-beta receptors types I and II and a mechanism that is distinct from clathrin-mediated endocytosis

Transforming growth factor-beta (TGF-beta) internalization was studied by monitoring the uptake of (125)I-TGF-beta1 in Mv1Lu cells, which endogenously express TGF-beta receptors types I (RI), II (RII), and III (RIII), and 293 cells transfected with RI and RII. At 37 degrees C internalization occurred rapidly, within 10 min of ligand addition. Internalization was optimal in 293 cells expressing both RI and RII. Internalization was prevented by phenylarsine oxide, a nonspecific inhibitor of receptor internalization, but was not affected by reagents that interfere with clathrin-mediated endocytosis such as monodansylcadaverine, K44A dynamin, and inhibitors of endosomal acidification. Electron microscopic examination of Mv1Lu cells treated with (125)I- TGF-beta1 at 37 degrees C indicated that internalization occurred via a noncoated vesicular mechanism. Internalization was prevented by prebinding cells with TGF-beta1 at 4 degrees C for 2 h prior to switching the cells to 37 degrees C. This was attributed to a loss of receptor binding, as indicated by a rapid decrease in the amount of TGF-beta1 bound to the cell surface at 37 degrees C and by a reduction in the labeling intensities of RI and RII in (125)I-TGF-beta1-cross-linking experiments. Mv1Lu or 293 (RI+RII) cells, prebound with TGF-beta1 at 4 degrees C and subsequently stripped of ligand by an acid wash, nevertheless initiated a signaling response upon transfer to 37 degrees C, suggesting that prebinding promotes formation of stable RI.RII complexes that can signal independently of ligand.