核受体辅助因子及其信号转导

类固醇激素、核受体及其辅助因子在细胞增殖、分化中起重要的作用。核受体与相应的配体结合后同细胞内的辅助激活因子CBP/P30 0、PCAF、P/CIP和SRC家族等结合形成的复合物能使组蛋白乙酰化促进基因的转录。当缺乏配体时核受体同辅助抑制因子SMRT、mSin3A及HAD1具有很强的结合力使组蛋白去乙酰化抑制基因的转录活性。MAPK、PKA、AP 1、Sap a、JAK/STAT、JAK信号传导中核受体辅助因子参与信号传导过程影响基因的转录     

肝X受体在体内胆固醇平衡中的作用

肝X受体(liver X receptors,LXRs)分为LXRα和LXRβ两种亚型,LXRs是配体激活的转录因子,属于核受体超家族中的一员,LXRs首先与维甲酸X受体(retinoid X receptor,RXR)形成LXR-RXR异二聚体,LXR-RXR与特异的LXR应答元件(liver Xreceptors response element,LXRE)结合从而激活基因表达。体内胆固醇平衡通过转录调节网来维持。在细胞水平,胆固醇合成和脂蛋白胆固醇吸收受到许多负反馈的调节。LXRs、法尼X受体(farnesoid X re-ceptor,FXR)以及其它核受体超家族成员一起促进胆固醇贮存、转运和分解代谢。这些调节代谢的核受体…     

过氧化物酶体增殖因子活化受体研究进展

过氧化物酶体增殖因子活化受体是配体依赖的细胞核激素受体超家族成员。这种受体广泛存在于体内多种组织中 ,在调控脂肪细胞、单核细胞分化成熟及肿瘤细胞增殖、分化中起重要作用。     

过氧化物酶体增殖物活化受体γ及其配体与肾脏疾病

1过氧化物酶体增殖物活化受体γ（peroxisome proliferators activated receptorγ,PPARγ）概述PPARs是一类由配体激活的核转录因子,属核激素受体超家族成员。     

类法尼醇X受体的功能及其配体的研究进展

类法尼醇X受体 (FXR)是一种细胞核激素受体 ,属孤儿核受体家族。胆汁酸和类法尼醇 (farnesoid)都是FXR的配体。FXR在调节胆固醇化合物中起重要作用 ,其作用机理与许多基因的调控有关。从印度香胶树中发现的天然产物guggul固醇 (GS)是一种FXR拮抗剂 ,具有很好的降脂作用。研究天然产物与FXR等细胞核受体的关系将会发现更多类似GS的降脂化合物     

磷酸化对核受体功能的调控研究进展

核受体是细胞核内一类能同相应的配体结合并调控特定基因表达的转录因子,参与细胞的分化、增殖和凋亡。研究表明,核受体的磷酸化与去磷酸化在多条信号途径中起着重要作用。本文围绕核受体的基本结构和功能、核受体发生磷酸化的部位、磷酸化对核受体转录活性的调节以及核受体磷酸化与癌症等几方面进行综述。     

骨代谢中甲状旁腺激素对相关蛋白和核因子κB受体活化因子的调节

背景：甲状旁腺激素是影响骨代谢功能轴最主要的因素。同时也是调控骨保护素和核因子κB受体活化因子配基表达的重要激素。 目的：通过查阅甲状旁腺激素对骨保护素、核因子κB受体活化因子配基调控作用的相关文章,并对其进行综述。 方法：以“甲状旁腺激素,骨保护蛋白,核因子κB受体活化因子”或“Parathyroid hormone, osteoprotegerin, receptor activator of nuclear factor κB ligand”为检索词,由第一作者通过计算机检索 CNKI、HighWire数据库中关于“甲状旁腺激素与骨保护素/核因子κB受体活化因子配基/核因子κB受体活化剂”的相关的论文报告。选择的文章内容与甲状旁腺激素对信号通路的影响有关、近期发表的文献,按纳入和排除标准对文献进行筛选,共纳入31篇文章。 结果与结论：甲状旁腺激素是调节骨代谢最主要的因素,通过增强破骨细胞活动增强而实现的。核因子κB受体活化因子配基是调节骨吸收的关键因子,它通过与核因子κB受体活化剂结合发挥功能。核因子κB受体活化因子配基与核因子κB受体活化剂结合后,启动核因子κB受体活化因子配基信号转导,骨保护素则与核因子κB受体活化因子配基竞争性结合核因子κB受体活化剂,核因子κB受体活化因子配基/骨保护素比值决定破骨细胞分化、成熟及功能。长时间、大强度的运动条件下,机体内甲状旁腺激素的变化是否对于骨保护素、核因子κB受体活化因子配基有影响,进而调节骨代谢的吸收与合成？还有待进一步的研究。     

Nurrl基因对多巴胺神经元的调控及其与多巴胺系统疾病的关系

Nurrl基因位于2q22-q23，全长9.822kb，由8个外显子和7个内含子组成，为一种机体早期应激反应基因。该基因编码产物为598个氨基酸组成的核蛋白受体，是类固醇激素和甲状腺激素核受体大家族中的一种寡核受体。近年来研究表明该基因对诱导中枢神经系统多巴胺神经元的发生、发育、分化及其成熟后功能维持起重要作用，而Parkinson病及精神分裂症与中枢多巴胺神经系统功能失调密切相关。故揭示该基因与中枢多巴胺神经元调控关系，对揭示Parkinson病及精神分裂症等多巴胺失调疾病的发病机制和治疗具有重要作用。     

核转录因子PPARs与代谢综合征

过氧化物酶体增殖物激活受体（PPARs)属Ⅱ型核受体超家族成员，是一类由配体激活的核转录因子，这类受体在体内分布广泛，参与脂肪细胞分化，调控脂类和糖的代谢，参与单核/巨噬细胞激活及肿瘤分化等多种过程，PPARs处于多种信号转导途径的交叉点，与代谢综合征关系密切。     

犬切牙压低移动过程中牙周组织骨保护素/核因子κB受体活化因子配体的表达

背景：骨保护素及核因子κB受体活化因子配体是调控破骨细胞生成和活化的关键因子,机械力可影响牙周膜细胞和成骨细胞骨保护素及核因子κB受体活化因子配体的表达。 目的：观察犬切牙压低移动过程中牙周组织中骨保护素/核因子κB受体活化因子配体的表达。 方法：采用微型种植体作为支抗,将犬切牙分别施加牵引力1,2,4,12周,并设置对照组进行比较。牵引后切取犬切牙连同牙龈及牙槽骨组织块,制作组织切片进行骨保护素及核因子κB受体活化因子配体免疫组织化学染色,用Image-Proplus软件半定量分析图像平均吸光度值。 结果与结论：与对照组相比,核因子κB受体活化因子配体和骨保护素分别在在施加牵引力1和2周表达最显著,其平均吸光度值在施加牵引力1和2周时可达到峰值(P < 0.05),随后逐渐下降,施加牵引力12周恢复至对照组水平。结果证实,正畸牙压低移动过程中核因子κB受体活化因子配体及骨保护素的表达变化规律与骨改建过程一致,骨保护素/核因子κB受体活化因子配体系统是牙周组织改建的重要调节因素。     

The nuclear receptor CAR modulates alcohol-induced liver injury

The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily and a sensor and detoxifier of both xenobiotics and endobiotics. Recent studies also show that CAR participates in metabolism of glucose and lipid, and has an important role in fatty liver disease and diabetes. In this study, we investigate the roles of CAR in chronic and acute alcohol-induced liver injuries. The results showed that absence of CAR in rodents led to significantly increased susceptibility to chronic alcohol-induced liver injury, which was accompanied with elevated hepatocyte apoptosis and fat accumulation. However, pre-activation of CAR by a CAR agonist, TCPOBOP, strongly enhanced the hepatic toxicity by both chronic and acute alcohol infusion in wild-type, but not in CAR(-/-) mice. Gene expression analyses indicated that CAR pre-activation and alcohol infusion synergistically decreased the expression of enzymes that metabolize the alcohol in liver. These results support a role of CAR in modulating alcoholic liver injury and imply a risk of synergistic liver toxicity induced by alcohol and CAR activation.     

Steroid hormone action in musculoskeletal cells involves membrane receptor and nuclear receptor mechanisms

Steroid hormones regulate target cells through traditional nuclear mechanisms as well as by membrane mechanisms. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 bind membrane receptors (mVDR) and mediate their effects on the physiological responses of musculoskeletal cells via protein kinase C (PKC). In cultures of costochondral growth plate chondrocytes, 1alpha,25(OH)2D3 binds the 1,25-mVDR in growth zone cells, activating phospholipase C (PLC), leading to diacylglycerol (DAG) production and PKC translocation to the plasma membrane. It also activates PLA2, increasing arachidonic acid release and prostaglandin synthesis. 24R,25(OH)2D3 binds its membrane receptor in resting zone chondrocytes, activating phospholipase D (PLD), and increasing DAG and PKC activity, but translocation does not occur. PLA2 activity is decreased, reducing arachidonic acid and prostaglandin production. 17Beta-estradiol (E2) activates PKC in both cartilage cells, but DAG is not involved. 1alpha,25(OH)2D3 and 24R,25(OH)2D3 also increase PKC in osteoblasts in a cell-specific manner. Antibodies to the 1,25-mVDR block PKC activation. Membrane-mediated events influence gene expression via signaling cascades, including the ERK1/2 MAP kinases. The ability of steroid hormones to initiate events nongenomically is important for regulation of matrix vesicle (MV) function in the extracellular matrix. MVs have mVDRs, but ligand binding inhibits PKC-zeta (PKCzeta) via a mechanism that differs from PKCalpha activation in the plasma membranes. Treatment of MVs from growth zone chondrocyte cultures with 1alpha,25(OH)2D3 releases stromelysin-1 (MMP-3) and increases TGF-beta activation. MMP-3 is also involved in proteoglycan degradation, facilitating calcification. 24R,25(OH)2D3 inhibits PKCzeta in MV from resting zone cell cultures and inhibits MMP-3 release. Chondrocytes and osteoblasts produce 1,25(OH)2D3, 24,25(OH)2D3, and E2; thus, locally produced steroids may function as autocrine regulators of matrix events, including matrix vesicle enzyme activity and matrix protein remodelling during longitudinal growth, calcification, and growth factor activation.     

Characterization of a putative nuclear receptor from Onchocerca volvulus

Steroids and retinoids are important regulators of development in invertebrates and vertebrates. The central mediators of action of these compounds are their cognate receptors, which together form a family of proteins known as the nuclear receptor family. Previous studies have demonstrated that the genome of Onchocerca volvulus encodes at least three members of the nuclear receptor family. Here, the characterization of one member of this family from O. volvulus, designated OvNR-2, is described. OvNR-2 was found to be most similar to a number of vertebrate retinoic acid receptors and to the Drosophila melanogaster EiP78c protein. Modeling studies suggest that OvNR-2 forms a boot shaped ligand-binding cavity of a shape and size that can bind steroids. Expression of the mRNA corresponding to OvNR-2 is tightly regulated in adult parasites, appearing only in the extended intrauterine microfilariae. The protein derived from expression of the OvNR-2 cDNA in a bacterial system is recognized by serum antibodies in a majority of individuals infected with O. volvulus.     

A neural mechanism of nuclear receptor expression and regionalization

Spatially restricted expression of genes by global circulating inducers (hormones, secreted proteins, growth factors, neuromodulators, etc.) was a prerequisite for the evolution of animals. Far from a random occurrence, it is a systematically occurring, certain event, implying that specific information is invested for it to happen. In this minireview, we show for the first time that the expression and regionalization takes place at the level of receptors via a neural mechanism and make an attempt to reconstruct the causal chain from neural signaling to expression of nuclear receptors.     

核受体辅助调节因子PELP1与肿瘤关系的研究进展

类固醇激素发挥生物学活性需要核受体辅助调节因子(NRC)的参与。脯氨酸-谷氨酸-亮氨酸富集蛋白1(PELP1)是新近发现的一种NRC,具有独特的分子结构和生物学功能。作为一种支架蛋白,PELPl既参与类固醇激素调控靶基因转录的基因组作用,又参与类固醇激素激活激酶信号系统的非基因组作用。PELP1在多种肿瘤组织中高表达,加快细胞周期、抑制细胞凋亡、诱导上皮-间质转化(EMT)、增强肿瘤细胞迁移侵袭能力和促进肿瘤细胞耐药,具有癌基因的特征,可能成为判断肿瘤预后的标志物和肿瘤治疗的作用靶点。     

The NR4A nuclear receptor family in eosinophils

It is well-known that many members of the family of nuclear receptors have been implicated in human diseases, and metabolic disorders in particular. The NR4A nuclear receptor family consists of three members, Nur77, Nurr1, and NOR1. All of these are orphan receptors, and Nur77 and NOR1 exert possible pathological roles in immune diseases through the modulation of leukocyte functions. CD30 stimulation, which induces eosinophil-specific apoptosis, markedly enhances expression of Nur77 and NOR1 in eosinophils. This suggests the possibility of pharmacological modulation of Nur77- or NOR1-specific apoptotic pathways via receptor-dependent transactivation. In this review, we discuss treatment of allergic diseases by low molecular weight compounds acting through the NR4A receptor family to cause eosinophil apoptosis. NR4A nuclear receptor genes were selected following comprehensive analysis of differentially expressed genes in eosinophils of atopic dermatitis patients compared with healthy volunteers.