核受体超家族介导基因调控的分子机制

核受体超家族由甾体激素、甲状腺激素、维甲酸、维生素D等化学信号的受体及配体未明的多种孤儿受体组成,该家族成员的主要功能是作为配体激活的转录因子,调控代谢、发育、生殖相关基因的表达。核受体与启动子和增强子上的激素应答元件及其它DNA序列特异性激活因子结合,而激活或阻遏靶基因的转录。核受体调控基因转录需要募集称为辅调控因子的蛋白分子,这些蛋白分子与核受体一起装配成多组分的复合物,它们可提供相关的酶促活性和脚手架功能。通过与基础转录机器的相互作用和对染色质结构的可逆性共价修饰等作用,辅调控因子调控核受体对靶基因转录的激活或阻遏。许多辅调控因子本身受到多条细胞内信号转导途径的调控。     

甾体激素对基因表达的调节作用

甾体激素调控基因表达是通过与激素受体结合,将受体转化激活,提高其与基因特定序列相结合的能力而诱导或阻抑靶细胞内特异基因的转录。与激素-受体复合物特异结合的DNA序列相当短,其作用类似基因转录的增强子,它可能与其它各种因素配合产生激素调节效应。     

核受体及核受体病

核受体为一类配体依赖性的转录调节蛋白,它们在一级结构及基因结构上具有同源性,属于核受体家族或甾体激素受体超家族。核受体异常或核受体病将导致靶细胞对相应激素的抵抗,在临床上产生激素不敏感或抵抗症。近年来,核受体病的分子缺陷及突变本质已得到初步揭示。     

雄激素受体的作用机制

主要概述了雄激素受体的作用机制,特别对影响雄激素受体特异性的因素进行探讨.雄激素受体（AR）属于甾体激素受体超家族,能通过配体依赖方式与特异的DNA序列结合,调控基因转录.     

中介因子复合体在基因转录调控中的作用

近二十年来,人类在不断探索基因转录调控的机制方面取得了长足的进步,其中包括对中介因子复合体(mediator complex)的克隆、鉴定及作用机制的研究。中介因子是由20多种不同蛋白亚基组成的复合体,广泛存在于各种真核生物的细胞中,并且与RNA聚合酶一起构成RNA聚合酶Ⅱ全酶。中介因子复合体可与转录因子和RNA聚合酶Ⅱ相互作用,因而在基因转录过程中发挥着桥梁的作用。中介因子复合体不但能够促进基因转录的激活,有时也能抑制基因转录。本文总结了中介因子复合体的组成、结构及功能方面的研究进展。     

神经活性甾体对神经元的作用

神经活性甾体是指神经组织中具有活性的甾体激素,根据甾体激素的作用机制可分为三类：（1）通过细胞表面离子通道型受体介导产生效应,这些受体包括GABAA受体,NMDA受体等。（2）通过G蛋白偶联的膜受体指导第二信使反应,再通过DNA结合蛋白,调节基因表达产生效应,（3）通过细胞内受体介导调控基因的表达产生效应,甾体激素的这些效应尤其是对离子通道型受体和G蛋白偶联型受体的调节作用,已引起重视。     

转录中介体复合物(Mediator complex)调控茉莉酸信号途径的新机制

转录中介体(Mediator)是由多个在进化上高度保守的亚基组成的蛋白复合物。在基因转录过程中,转录中介体分别与基因特异的转录因子和RNA聚合酶II相互作用,广泛参与二者之间的信息传递,被称为真核生物基因转录的中央控制器。在植物激素信号转导研究中,人们主要关注激素特异的转录因子的作用,但对于转录中介体的功能及作用机理     

真核生物rRNA基因的转录调节

核糖体RNA(rRNA）基因的转录直接决定着细胞核糖体的生物发生,而后者与细胞的生长、增殖等行为相适应.研究发现,rRNA基因转录以RNA聚合酶Ⅰ（Pol Ⅰ）为核心,有多种因子参与,并受到多种调控因子的严密调节控制;各调控因子不仅均有自己特异的作用位点,而且又彼此关联、相辅相成.本文在简要介绍真核生物rRNA基因转录基本过程与涉及的主要因子的基础上,重点阐述了rRNA基因转录的主要调节方式,包括ERK、mTOR和JNK等信号转导通路对转录因子磷酸化的影响;转录因子的乙酰化;细胞周期相关因子和其它因子的多种作用方式等. 概括起来看,真核生物rRNA基因转录调节的核心机制是调节转录因子间及转录因子与DNA间的相互作用或影响染色质结构,从而实现对rRNA基因转录的调控,以满足特定生理/病理状况下细胞对rRNA量的要求.     

CDK12主要生理功能与其在肿瘤发生中作用的研究进展

周期蛋白依赖性激酶(cyclin-dependent kinase, CDK)是细胞周期和基因转录的关键调节因子,其调控异常是促进肿瘤发生的重要因素。CDK12是一种与转录相关的周期蛋白依赖性激酶,可使RNA聚合酶Ⅱ碳端氨基酸(carboxy terminal domain of RNA polymeraseⅡ, RNA pol II CTD)中的丝氨酸磷酸化,并参与多种细胞生理过程,如DNA损伤反应、细胞增殖和分化以及m RNA剪接和转录前m RNA加工等。此外, CDK12编码基因的突变将导致多种细胞过程调控异常,基因不稳定性增加,这都可能促进肿瘤的发生发展。本文将重点讨论细胞中CDK12调节转录调控、RNA剪接、细胞成熟和分化、DNA损伤修复(DNA damage repair, DDR)的机制以及其基因突变对于正常细胞的影响,旨在阐明CDK12的主要生理功能及其在肿瘤发生发展中的作用,为临床各类肿瘤的靶向药物研究提供帮助。     

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。     

Substituted phenyl as a steroid A-ring mimetic: Providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands

A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors.     

The ecdysteroid receptor

Summary

The steroid molting hormone of insects and other arthropods regulates gene activity in target tissues through its association with a specific, high affinity receptor protein. In this review we summarize recent advances in several areas of ecdysteroid receptor research, including efforts to characterize and purify the receptor protein, cytochemical studies of its tissue distribution and subcellular localization during development, and current molecular genetic studies ecdysteroid action.     

雄激素和雌激素受体药物筛选方法的研究进展

雄激素和雌激素受体通过与相应激素特异性结合促进细胞分化和组织生长,发挥重要的生理功能,其功能失调可诱发多种疾病。雄激素和雌激素受体的选择性调节剂是治疗相关疾病的重要药物。基于基因组学、分子生物学、细胞生物学和生物信息学等最新研究成果而发展形成的实验技术或方法被用于新型雄激素和雌激素受体调节剂的筛选,显著加快了新药开发的进程。     

Analysis of 3D models of octopus estrogen receptor with estradiol: evidence for steric clashes that prevent estrogen binding

Relatives of the vertebrate estrogen receptor (ER) are found in Aplysia californica, Octopus vulgaris, Thais clavigera, and Marisa cornuarietis. Unlike vertebrate ERs, invertebrate ERs are constitutively active and do not bind estradiol. To investigate the molecular basis of the absence of estrogen binding, we constructed a 3D model of the putative steroid-binding domain on octopus ER. Our 3D model indicates that binding of estradiol to octopus ER is prevented by steric clashes between estradiol and amino acids in the steroid-binding pocket. In this respect, octopus ER resembles vertebrate estrogen-related receptors (ERR), which have a ligand-binding pocket that cannot accommodate estradiol. Like ERR, octopus ER also may have the activation function 2 domain (AF2) in a configuration that can bind to coactivators in the absence of estrogens, which would explain constitutive activity of octopus ER.     

降钙素基因相关肽家族受体及其受体活性修饰蛋白

降钙素基因相关肽家族是一类多功能的激素家族 ,参与人体的多种生物学功能 ,与多种疾病有关。降钙素基因相关肽受体包括降钙素受体 (CTR)和降钙素受体样受体 (CRLR) ,CTR可以独自与降钙素结合 ,而CRLR必须与一组称作受体活性修饰蛋白 (RAMPs)的蛋白质共同作用才能发挥生物学功能。综述CTR的研究概况及CRLR与RAMPs相互作用的机制和表达调控 ,以期为人们设计新型药物提供参考。     

Proteinase-activated receptors, nucleotide P2Y receptors, and μ-opioid receptor-1B are under the control of the type I transmembrane proteins p23 and p24A in post-Golgi trafficking

We recently characterized the proteinase-activated receptor (PAR)-2, a G protein-coupled receptor (GPCR), as the first cargo protein recognized by p24A. Here, we demonstrate that p24A binds to several other GPCRs, including PAR-1, the nucleotide receptors P2Y(1), P2Y(2), P2Y(4), and P2Y(11), as well as the μ-opioid receptor 1B. The acidic amino acid residues Glu and Asp at the second extracellular loop of GPCRs are essential for interaction with p24A. p23, another member of the p24 family, also interacts with GPCRs, similar to p24A. However, p23 shows a delayed dissociation from PAR-2 after activation of PAR-2, compared to the dissociation between PAR-2 and p24A. p24A and p23 arrest both P2Y(4) receptor and μ-opioid receptor 1B at the intracellular compartments, as observed for PAR-2. A comparable result was obtained when we studied primary rat astrocytes in culture. Over-expression of the N-terminal p24A fragment impairs PAR-2 resensitization in astrocytes that extends our findings to a native system. In summary, we demonstrate that p24A and p23 are specific cargo receptors of GPCRs and differentially control GPCR trafficking in the biosynthetic pathway, and thereby, p24A and p23 regulate GPCR signaling in astrocytes.     

Ago-Allosteric Modulation and Other Types of Allostery in Dimeric 7TM Receptors

Conventionally, an allosteric modulator is neutral in respect of efficacy and binds to a receptor site distant from the orthosteric site of the endogenous agonist. However, recently compounds being ago-allosteric modulators have been described i.e., compounds acting both as agonists on their own and as enhancers for the endogenous agonists in both increasing agonist potency and providing additive efficacy—superagonism. The additive efficacy can also be observed with agonists, which are neutral or even negative modulators of the potency of the endogenous ligand. Based on the prevailing dimeric concept for 7TM receptors, it is proposed that the ago-allosteric modulators bind in the orthosteric binding site, but–importantly–in the “other” or allosteric protomer of the dimer. Hereby, they can act both as additive co-agonists, and through intermolecular cooperative effects between the protomers, they may influence the potency of the endogenous agonist. It is of interest that at least some endogenous agonists can only occupy one protomer of a dimeric 7TM receptor complex at a time and thereby they leave the orthosteric binding site in the allosteric protomer free, potentially for binding of exogenous, allosteric modulators. If the allosteric modulator is an agonist, it is an ago-allosteric modulator; if it is neutral, it is a classical enhancer. Molecular mapping in hetero-dimeric class-C receptors, where the endogenous agonist clearly binds only in one protomer, supports the notion that allosteric modulators can act through binding in the “other” protomer. It is suggested that for the in vivo, clinical setting a positive ago-allosteric modulator should be the preferred agonist drug.     

新型抗抑郁药物分子靶标研究进展

抑郁症是一种严重的精神障碍疾病,其发病机制复杂。近年来随着对抑郁症发病机制的深入研究,发现了一些基于非单胺递质的 新型抗抑郁药物分子靶标。综述N -甲基-D-天冬氨酸（NMDA）受体、促肾上腺皮质激素释放因子（CRF）受体、阿片受体、γ-氨基丁 酸B(GABAB) 受体、乙酰胆碱受体等抗抑郁药物作用的新靶标及其相应分子机制研究进展,为开发高效、安全的抗抑郁症新药提供参考。     

The insulin-binding domain of insulin receptor is encoded by exon 2 and exon 3.

Insulin receptors are disulfide-linked oligotetramers composed of two heterodimers each containing a 130-kDa alpha subunit and a 90-kDa beta subunit. Insulin binds to the extracellular alpha subunit, and in the process stimulates the autophosphorylation of the beta subunit and the expression of tyrosine kinase activity. Studies combining the use of photoaffinity labeling and immunoprecipitation with anti-peptide antibody have directly demonstrated that the cysteine-rich domain, encoded by exon 3, in the alpha subunit is part of the insulin-binding site of the receptor. Experiments with chimeric insulin receptors and chimeric insulin-like growth factor I receptors have confirmed that the cysteine-rich domain constitutes a part of the insulin-binding site. In addition, results from these experiments suggest that the N-terminal sequence, encoded by exon 2, in the alpha subunit also participates in insulin binding. In this review it is proposed that, assuming two insulin-binding sites per each holoreceptor oligotetramer, each insulin-binding domain may contain respectively two sub-domains for hydrophobic and charge contact with insulin, and that high-affinity binding would require the interaction of both subunits with the possibility of each subunit reciprocally contributing one of the sub-domains.