孤儿核受体类固醇生成因子1

孤儿核受体是核受体超家族中较独特的成员,它参与了糖类、脂类及胆固醇和类固醇激素的代谢,可能是体内细胞基本功能的重要调节因子。孤儿核受体SF－1最初作为肾上腺和性腺中的P450羟化酶必需的调节子而被鉴定,在类固醇组织、垂体和下丘脑腹内侧核均有表达,SF01在基础结构上具有不同于其他核受体的特征结构域,并广泛参与许多基因如类固醇合成酶类、Muellerian抑制性物质、黄体生成素β亚基启动子等的表达调控,基因剔除实验证实SF－1是肾上腺类固醇合成和性别分化中的一个关键调节因子。     

早幼粒白血病蛋白核体与病毒感染

早幼粒白血病蛋白核体（promyelocytic leukaemia nuclear bodies,PML-NBs）是哺乳动物细胞中普遍存在的一种动态的细胞核亚结构,参与DNA损伤与修复、细胞衰老与凋亡、基因表达调控以及肿瘤发生与抑制等多种重要的细胞活动。研究表明,PML-NBs也是多种病毒入侵细胞的作用靶点。PML-NBs通过介导细胞固有免疫反应或者作为细胞干扰素信号通路元件参与宿主细胞的抗病毒防御活动。该文以几种DNA和RNA病毒为例,综述了在病毒感染过程中PML-NBs与病毒的相互作用以及这些相互作用的功能意义,从而揭示PML-NBs在抵御病毒感染和免疫反应中的重要作用,并提出运用病毒单分子实时示踪（Single-virus Tracking）这一新技术深入研究PML-NBs在病毒感染中作用的可行性。     

核孤儿受体在胆固醇分解代谢过程中的调控作用

由胆固醇合成胆汁酸有两条途径。一条是经典途径或中性途径[1] ,也是合成胆汁酸最主要的途径 ,其限速反应为胆固醇 7α 羟化酶 (由Ｃｙｐ7ａ编码 )催化胆固醇羟化为 7α 羟胆固醇的反应。近几年发现另一条胆汁酸合成的酸性途径[2 ] ,这一途径开始于胆固醇转变为氧固醇 (ｏｘｙｓｔｅｒｏｌ) ,然后经氧固醇 7α 羟化酶 (由Ｃｙｐ7ｂ编码 )催化产生 7α 羟氧固醇化合物 ,再融入胆汁酸合成经典途径的下游步骤。由于胆固醇在体内有重要作用 ,有效调节胆固醇分解代谢以维持胆固醇水平的动态平衡十分重要。研究发现 ,胆汁酸以及合成过程中的中间产…     

FLASH Meets Nuclear Bodies: CD95 Receptor Signals via a Nuclear Pathway

The CD95 receptor signals via assembly of a multi-protein complex termed death-inducing signaling complex (DISC) which triggers activation of receptor-bound caspase-8/FLICE molecules. Most cells (type II cells) depend on a mitochondrial amplification pathway to commit apoptosis upon CD95 activation. The caspase-8-binding protein FLICE-associated huge protein (FLASH) has been previously implicated in the regulation of caspase-8 activation at the DISC. However, recent findings demonstrated that FLASH is a Cajal body component and regulates progression through S-phase of the cell cycle in the nucleus. Our recent work identified FLASH as binding partner of the PML nuclear body (PML NB) constituent Sp100 and demonstrated that FLASH partially localizes to PML NBs. Upon CD95 activation FLASH exits the nucleus and translocates to mitochondria where it meets caspase-8 to promote its activation. Our findings reconcile conflicting views on FLASH localization and its role in apoptosis regulation, and suggest that CD95 signals via a nuclear pathway. Potential implications of our findings for understanding FLASH function are discussed.     

Explosive Lineage-Specific Expansion of the Orphan Nuclear Receptor HNF4 in Nematodes

The nuclear receptor superfamily expanded in at least two episodes: one early in metazoan evolution, the second within the vertebrate lineage. An exception to this pattern is the genome of the nematode Caenorhabditis elegans, which encodes more than 270 nuclear receptors, most of them highly divergent. We generated 128 cDNA sequences for 76 C. elegans nuclear receptors, confirming that these are active genes. Among these numerous receptors are 13 orthologues of nuclear receptors found in arthropods and/or vertebrates. We show that the supplementary nuclear receptors (supnrs) originated from an explosive burst of duplications of a unique orphan receptor, HNF4. This origin has specific implications for the role of ligand binding in the function and evolution of the nematode supplementary nuclear receptors. Moreover, the supplementary nuclear receptors include a group of very rapidly evolving genes found primarily on chromosome V. We propose a model of lineage-specific duplications from a chromosome on which duplication and substitution rates are highly increased. Our results provide a framework to study nuclear receptors in nematodes, as well as to consider the functional and evolutionary consequences of lineage-specific duplications.Reviewing Editor: Dr. Nicolos Galtier     

Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

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Phosphorothioate Antisense Oligonucleotides Induce the Formation of Nuclear Bodies

Antisense oligonucleotides are powerful tools for the in vivo regulation of gene expression. We have characterized the intracellular distribution of fluorescently tagged phosphorothioate oligodeoxynucleotides (PS-ONs) at high resolution under conditions in which PS-ONs have the potential to display antisense activity. Under these conditions PS-ONs predominantly localized to the cell nucleus where they accumulated in 20–30 bright spherical foci designated phosphorothioate bodies (PS bodies), which were set against a diffuse nucleoplasmic population excluding nucleoli. PS bodies are nuclear structures that formed in cells after PS-ON delivery by transfection agents or microinjection but were observed irrespectively of antisense activity or sequence. Ultrastructurally, PS bodies corresponded to electron-dense structures of 150–300 nm diameter and resembled nuclear bodies that were found with lower frequency in cells lacking PS-ONs. The environment of a living cell was required for the de novo formation of PS bodies, which occurred within minutes after the introduction of PS-ONs. PS bodies were stable entities that underwent noticeable reorganization only during mitosis. Upon exit from mitosis, PS bodies were assembled de novo from diffuse PS-ON pools in the daughter nuclei. In situ fractionation demonstrated an association of PS-ONs with the nuclear matrix. Taken together, our data provide evidence for the formation of a nuclear body in cells after introduction of phosphorothioate oligodeoxynucleotides.     

Germ Cell Nuclear Factor: An Orphan Receptor in Search of a Function

Germ Cell Nuclear Factor (GCNF) is an orphan member of the nuclearreceptor gene superfamily. Much has been understood about thefunctioning of GCNF which represents a candidate receptor fora novel hormonal signalling pathway. GCNF is not closely relatedto other members of the nuclear receptor superfamily and formsits own branch within the superfamily tree. It has a uniqueexpression pattern that spans both embryonic and adult stagesof development. In the adult, it is expressed in the germ cells:oocytes and spermatogenic cells as well as specific neuronalcells within the brain. In the embryo, GCNF expression is turnedon after gastrulation in all germ layers the ectoderm, mesodermand endoderm. An antero-posterior gradient of GCNF is establishedin the neuroectoderm of the embryo, suggesting a role in regulationof neuronal and germ cell development. Regulation of physiologicalprocesses by a nuclear receptor is achieved through regulationof gene expression. GCNF is the only nuclear receptor to specifcallybind to DR0 hormone response elements to regulate gene expression.In the absense of a ligand, GCNF represses gene expression.GCNF is capable of regulating the expression of the protaminegenes in a response element-dependent manner. At present theligand for GCNF is unknown, but it is hypothesized that GCNFis a receptor for a novel hormonal signalling pathway that effectsits biological response by regulating the expression of a subsetof genes containing DR0 response elements.     

Association of Nuclear Matrix Proteins with Granular and Threaded Nuclear Bodies in Cell Lines Undergoing Apoptosis

The granules which appear in the nucleolar area in apoptotic HL-60 cells after camptothecin administration (Zweyeret al., Exp. Cell Res.221, 27–40, 1995) were detected also in several other cell lines induced to undergo apoptosis by different stimuli, such as MOLT-4 treated with staurosporine, K-562 incubated with actinomycin D, P-815 exposed to temperature causing heat shock, Jurkat cells treated with EGTA, U-937 growing in the presence of cycloheximide and tumor necrosis factor-α, and HeLa cells treated with etoposide. Using immunoelectron microscopy techniques, we demonstrate that, besides the already described nuclear matrix proteins p125 and p160, these granules contain other nucleoskeletal polypeptides such as proliferating cell nuclear antigen, a component of ribonucleoprotein particles, a 105-kDa constituent of nuclear spliceosomes, and the 240-kDa nuclear mitotic apparatus-associated protein referred to as NuMA. Moreover, we also found in the granules SAF-A/hn-RNP-U and SATB1 proteins, two polypeptides that have been reported to bind scaffold-associated regions DNA sequencesin vitro,thus mediating the formation of looped DNA structuresin vivo.Fibrillarin and coilin are not present in these granules or the PML protein. Thus, the granules seen during the apoptotic process apparently are different from coiled bodies or other types of nuclear bodies. Furthermore, these granules do not contain chromatin components such as histones and DNA. Last, Western blotting analysis revealed that nuclear matrix proteins present in the granules are not proteolytically degraded except for the NuMA polypeptide. We propose that these granules might represent aggregates of nuclear matrix proteins forming during the apoptotic process. Moreover, since the granules are present in several cell lines undergoing apoptosis, they could be considered a previously unrecognized morphological hallmark of the apoptotic process.