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The seven-transmembrane receptor Smoothened cell-autonomously induces multiple ventral cell types

NATURE NEUROSCIENCE 2000年第1期3卷 41-46页

作者： Hynes, M Ye, WL Wang, K Stone, D Murone, M de Sauvage, F Rosenthal, A Genentech Inc Dept Neurosci San Francisco CA 94080 USA Genentech Inc Dept Mol Oncol San Francisco CA 94080 USA

Sonic Hedgehog (Shh) is a secreted protein that controls cell fate and mitogenesis in the developing nervous system. Here we show that a constitutively active form of Smoothened (Smo-M2) mimics concentration-dependent actions of Shh in the;developing neural tube, including activation of ventral marker genes (HNF3 beta, patched, Nkx2.2, netrin-1), suppression of dorsal markers (Pax-3, Gli-3, Ephrin A5) and induction of ventral neurons (dopaminergic, serotonergic) and ventrolateral motor neurons (Islet-1+, Islet-2+, HB9+) and interneurons (Engrailed-1+, CHX10+). Furthermore, Smo-M2's patterning activities were cell autonomous, occurring exclusively in cells expressing Smo-M2 These findings suggest that Smo is a key signaling component in the Hh receptor and that Shh patterns the vertebrate nervous system as a morphogen, rather than through secondary relay signals.

关键词：氨基酸取代抗原分化/代谢躯体发育模式/遗传学躯体发育模式/生理学脑/细胞学脑/胚胎学脑/代谢胚胎诱导基因表达调控发育期基因报告猬蛋白质类中间神经元/细胞学中间神经元/代谢小鼠转基因运动神经元/细胞学运动神经元/代谢神经嵴/细胞学神经嵴/胚胎学神经嵴/代谢蛋白质类/生理学受体细胞表面/遗传学受体细胞表面/代谢受体细胞表面/生理学受体 G-蛋白偶联信号传导/遗传学信号传导/生理学脊髓/细胞学脊髓/胚胎学反式激活因子类转染动物鸡胚小鼠

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Genetic analysis demonstrates a direct link between Rho signaling and nonmuscle myosin function during Drosophila morphogenesis

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GENETICS 2000年第3期155卷 1253-1265页

作者： Halsell, SR Chu, BI Kiehart, DP Duke Univ Med Ctr Dept Cell Biol Durham NC 27710 USA

A dynamic actomyosin cytoskeleton drives many morphogenetic events. Conventional nonmuscle myosin-II (myosin) is a key chemomechanical motor that drives contraction of the actin cytoskeleton. We have explored the regulation of myosin activity by performing genetic screens to identify gene products that collaborate with myosin during Drosophila morphogenesis. Specifically, we screened for second-site noncomplementors of a mutation in the zipper gene that encodes the nonmuscle myosin-II heavy chain. We determined. that a single missense mutation in the zipper(Ebr) allele gives rise to its sensitivity to second-site noncomplementation. Mie then identify the Rho signal transduction path way as necessary for proper myosin function. First we show that a lethal P-element insertion interacts genetically with zipper. Subsequently we show that this second-site noncomplementing mutation disrupts the RhoGEF2 locus. Next, we show that two EMS-induced mutations, previously shown to interact genetically with zipper(Ebr) disrupt the RhoA locus. Further, we have identified their molecular lesions and determined that disruption of the carboxyl-terminal CaaX box gives rise to their mutant phenotype. Finally, we show that RhoA mutations themselves can be utilized in genetic screens. Biochemical and cell analyses suggest that Rho signal transduction regulated the activity of myosin. Our studies provide direct genetic proof of the biological relevance of regulation of myosin by Rho signal transduction in an intact metazoan.

关键词：等位基因染色体/遗传学果蝇蛋白质类黑腹果蝇/胚胎学黑腹果蝇/遗传学黑腹果蝇/代谢遗传互补测验鸟嘌呤核苷酸交换因子类/遗传学鸟嘌呤核苷酸交换因子类/代谢免疫印迹法膜蛋白质类/遗传学形态发生/遗传学突变误义肌球蛋白重链/遗传学肌球蛋白类/代谢物理染色体图蛋白质结构三级/遗传学信号传导/遗传学 ρAGTP结合蛋白质/遗传学动物

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Mechanism of caffeine-induced checkpoint override in fission yeast

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MOLECULAR AND CELLULAR BIOLOGY 2000年第12期20卷 4288-4294页

作者： Moser, BA Brondello, JM Baber-Furnari, B Russell, P Scripps Res Inst Dept Mol Biol La Jolla CA 92037 USA Scripps Res Inst Dept Cell Biol La Jolla CA 92037 USA

Mitotic checkpoints restrain the onset of mitosis (M) when DNA is incompletely replicated or damaged. These checkpoints are conserved between the fission yeast Schizosaccharomyces pombe and mammals. In both types of organisms, the methylxanthine caffeine overrides the synthesis (S)-M checkpoint that couples mitosis to completion of DNA S phase. The molecular target of caffeine was sought in fission yeast. Caffeine prevented activation of Cds1 and phosphorylation of Chk1, two protein kinases that enforce the S-M checkpoint triggered by hydroxyurea. Caffeine did not inhibit these kinases in vitro but did inhibit Rad3, a kinase that regulates Cds1 and Chk1. In accordance with this finding, caffeine also overrode the G(2)-M DNA damage checkpoint that requires Rad3 function. Rad3 coprecipitated with Cds1 expressed at endogenous amounts, a finding that supports the hypothesis that Rad3 is involved in direct activation of Cds1.

关键词：咖啡因/药理学 DNA损伤/药物作用 DNA复制/药物作用 DNA结合蛋白质类内切核酸酶类/遗传学内切核酸酶类/代谢有丝分裂/药物作用有丝分裂/遗传学磷酸二酯酶抑制剂/药理学蛋白激酶类/遗传学蛋白激酶类/代谢蛋白质丝氨酸苏氨酸激酶裂殖酵母菌属/细胞学裂殖酵母菌属/遗传学裂殖酵母菌属/代谢非洲粟酒人体酵母蛋白质类信号传导/药物作用信号传导/遗传学动物

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Leukaemia disease genes: large-scale cloning and pathway predictions

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NATURE GENETICS 1999年第3期23卷 348-353页

作者： Li, JY Shen, H Himmel, KL Dupuy, AJ Largaespada, DA Nakamura, T Shaughnessy, JD Jenkins, NA Copeland, NG NCI Mammalian Genet Lab ABL Basic Res Program Frederick Canc Res & Dev Ctr Frederick MD 21701 USA Univ Minnesota Ctr Canc Dept Genet Cell Biol & Dev Minneapolis MN USA JST PRESTO Tokyo Japan Japanese Fdn Canc Res Tokyo Japan Univ Arkansas Med Sci Dept Med Little Rock AR 72205 USA

Retroviral insertional mutagenesis in BXH2 and AKXD recombinant inbred mice induces a high incidence of myeloid or B- and T-cell leukaemia1, 2 and the proviral integration sites in the leukaemias provide powerful gene... 详细信息

Retroviral insertional mutagenesis in BXH2 and AKXD recombinant inbred mice induces a high incidence of myeloid or B- and T-cell leukaemia^1,² and the proviral integration sites in the leukaemias provide powerful genetic tags for disease gene identification. Some of the disease genes identified by proviral tagging are also associated with human disease^3,^4,⁵, validating this approach for human disease gene identification. Although many leukaemia disease genes have been identified over the years, many more remain to be cloned⁶. Here we describe an inverse PCR (IPCR) method for proviral tagging that makes use of automated DNA sequencing and the genetic tools provided by the Mouse Genome Project, which increases the throughput for disease gene identification. We also use this IPCR method to clone and analyse more than 400 proviral integration sites from AKXD and BXH2 leukaemias and, in the process, identify more than 90 candidate disease genes. Some of these genes function in pathways already implicated in leukaemia, whereas others are likely to define new disease pathways. Our studies underscore the power of the mouse as a tool for gene discovery and functional genomics.

关键词：染色体/遗传学克隆分子/方法表达的序列标记基因组白血病实验性/遗传学淋巴瘤/遗传学小鼠近交系诱变插入癌基因/遗传学物理染色体图聚合酶链反应/方法原病毒/遗传学可重复性结果逆转录病毒科/遗传学敏感性与特异性序列同源性核酸信号传导/遗传学肿瘤细胞培养的动物人类小鼠

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Modeling transcriptional control in gene networks - Methods, recent results, and future directions

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BULLETIN OF MATHEMATICAL BIOLOGY 2000年第2期62卷 247-292页

作者： Smolen, P Baxter, DA Byrne, JH Univ Texas Sch Med Dept Neurobiol & Anat WM Keck Ctr Neurobiol Learning & Memory Houston TX 77225 USA

Mathematical models are useful for providing a framework for integrating data and graining insights into the static and dynamic behavior of complex biological systems such as networks of interacting genes. We review the dynamic behaviors expected from model gene networks incorporating common biochemical motifs, and we compare current methods for modeling genetic networks. A common modeling technique, based on simply modeling genes as ON-OFF switches, is readily implemented and allows rapid numerical simulations. However, this method may predict dynamic solutions that do not correspond to those seen when systems are modeled with a more detailed method using ordinary differential equations. Until now, the majority of gene network modeling studies have focused on determining the types of dynamics that can be generated by common biochemical motifs such as feedback loops or protein oligomerization. For example, these elements can generate multiple stable states for gene product concentrations, state-dependent responses to stimuli, circadian rhythms and other oscillations, and optimal stimulus frequencies for maximal transcription. In the future, as new experimental techniques increase the ease of characterization of genetic networks, qualitative modeling will need to be supplanted by quantitative models for specific systems. (C) 2000 Society for Mathematical Biology.

关键词：大肠杆菌/遗传学反馈基因表达调控记忆模型遗传学海胆纲/遗传学信号传导/遗传学随机过程转录因子/遗传学转录遗传/遗传学动物人类

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Fusion genetic analysis of gibberellin signaling mutants

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PLANT JOURNAL 2000年第5期22卷 427-438页

作者： Raventos, D Meier, C Mattsson, O Jensen, AB Mundy, J Inst Mol Biol DK-1353 Copenhagen K Denmark

A fusion genetic strategy was used to identify gibberellin (GA) signaling mutants in transgenic Arabidopsis expressing the beta-glucuronidase (GUS) and firefly luciferase (LUC) reporter genes under control of the GA-responsive GASA1 promoter. Initial analyses determined the spatial and temporal patterns of reporter expression, and showed that reporter induction by GA was antagonized by ABA. gamma-Irradiated M-2 progeny with altered reporter activities were identified by LUC bioimaging followed by GUS assays and northern hybridization of the endogenous GASA1 mRNA. Genetic analysis showed that three mutants, which overexpressed both reporters and endogenous GASA1, were caused by recessive (goe1 and goe2, for GASA over-expressed) and semi-dominant (goe3) mutations at different loci. These mutants are altered in their sensitivity to GA and the GA biosynthetic inhibitor paclobutrazol, and in the expression of several GA signaling related genes.

关键词：碱基序列 DNA引物赤霉素类/遗传学赤霉素类/代谢葡糖醛酸糖苷酶/遗传学萤光素酶类/遗传学发光测定法突变植物生长调节物/药理学植物基因修饰重组融合蛋白质类/遗传学信号传导/遗传学三唑类/药理学

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Induction of pathogenic sets of genes in macrophages and neurons in neuroAIDS

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AMERICAN JOURNAL OF PATHOLOGY 2003年第6期162卷 2041-2057页

作者： Roberts, ES Zandonatti, MA Watry, DD Madden, LJ Henriksen, SJ Taffe, MA Fox, HS Scripps Res Inst Dept Neuropharmacol La Jolla CA 92037 USA

The etiology of the central nervous system (CNS) alterations after human immunodeficiency virus (HIV) infection, such as dementia and encephalitis, remains unknown. We have used microarray analysis in a monkey model of neuroAIDS to identify 98 genes, many previously unrecognized in lentiviral CNS pathogenesis, whose expression is significantly upregulated in the frontal lobe of simian immunodeficiency virus-infected brains. Further, through immunohistochemical. illumination, distinct classes of genes were found whose protein products localized to infiltrating macrophages, endothelial cells and resident glia, such as CD163, Glut5, and ISG15. In addition we found proteins Induced in cortical neurons (ie, cyclin D3, tissue transglutaminase, alpha1-antichymotrypsin, and STAT1), which have not previously been described as participating in simian immunodeficiency virus or HIV-related CNS pathology. This molecular phenotyping in the infected brains revealed pathways promoting entry of macrophages into the brain and their subsequent detrimental effects on neurons. These data support the hypothesis that in HIV-induced CNS disease products of activated macrophages and astrocytes lead to CNS dysfunction by directly damaging neurons, as well as by induction of altered gene and protein expression profiles in neurons themselves which are deleterious to their function. (Am J Pathol 2003, 162:2041-2057)

关键词：抗原呈递/遗传学脑/代谢脑/病理学脑/病毒学细胞周期/遗传学细胞分化/遗传学细胞分裂/遗传学细胞运动中枢神经系统疾病/遗传学中枢神经系统疾病/代谢中枢神经系统疾病/病理学细胞骨架/遗传学基因表达谱免疫系统/代谢免疫组织化学原位杂交炎症/遗传学炎症/代谢炎症/病理学干扰素类/药理学猕猴巨噬细胞/代谢巨噬细胞/病毒学小神经胶质细胞/代谢小神经胶质细胞/病毒学单核细胞/病理学神经元/代谢神经元/病毒学寡核苷酸序列分析蛋白质类/遗传学 RNA/遗传学 RNA/代谢信号传导/遗传学猴获得性免疫缺陷综合征/遗传学猴获得性免疫缺陷综合征/代谢猴获得性免疫缺陷综合征/病理学猴免疫缺陷病毒转录遗传动物

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Insulin-mediated cell proliferation and survival involve inhibition of c-Jun N-terminal kinases through a phosphatidylinositol 3-kinase- and mitogen-activated protein kinase phosphatase-1-dependent pathway

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ENDOCRINOLOGY 2000年第3期141卷 922-931页

作者： Desbois-Mouthon, C Cadoret, A Blivet-Van Eggelpoël, MJ Bertrand, F Caron, M Atfi, A Cherqui, G Capeau, J Univ Paris 06 INSERM U402 F-75571 Paris 12 France Hop St Antoine INSERM U482 F-75571 Paris 12 France

We previously reported that long term treatment with insulin led to sustained inhibition of c-Jun N-terminal kinases (JNKs) in CHO cells overexpressing insulin receptors. Here we investigated the sig -naling molecules involved in insulin inhibition of JNKs, focusing on phosphatidylinositol 3-kinase (PI 3-K) and mitogen-activated protein kinase phosphatase-1 (MKP-1). In addition, we examined the relevance of JNK inhibition for insulin-mediated proliferation and survival. Insulin inhibition of JNKs was mediated by PI 3-K, as it was blocked by wortmannin and LY294002 and required the de novo synthesis of a phosphatase(s), as it was abolished by orthovanadate and actinomycin D. MKP-1 was a good candidate because 1) insulin stimulation of MKP-1 expression correlated with insulin inhibition of JNKs: 2) insulin stimulation of MKP-1 expression, like insulin inhibition of JNKs, was mediated by PI 3-K;and 3) the transient expression of an antisense MKP-1 RNA reduced the insulin inhibitory effect on JNKs. The overexpression of a dominant negative JNK1 mutant increased insulin stimulation of DNA synthesis and mimicked the protective effect of insulin against serum withdrawal-induced apoptosis. The overexpression of wild-type JNK1 or antisense MKP-1 RNA reduced the proliferative and/or antiapoptotic responses to insulin. Altogether, these results demonstrate that insulin inhibits JNKs through a PI 3-K and MW-1-dependent pathway and provide evidence for a key role for JNK inhibition in insulin regulation of proliferation and survival.

关键词： 1-磷脂酰肌醇3-激酶/遗传学 1-磷脂酰肌醇3-激酶/代谢细胞凋亡/药物作用印迹法蛋白质 CHO细胞细胞计数/药物作用细胞周期蛋白质类细胞分裂/生理学细胞存活/生理学细胞培养的仓鼠亚科 DNA/生物合成 DNA/遗传学糖原/生物合成即早蛋白质类/遗传学即早蛋白质类/代谢胰岛素/生理学 JNK丝裂原活化蛋白激酶类丝裂原激活蛋白激酶类/拮抗剂和抑制剂丝裂原激活蛋白激酶类/遗传学质粒/遗传学信号传导/遗传学信号传导/生理学转染/遗传学动物大鼠

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BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control

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IMMUNITY 2000年第2期13卷 199-212页

作者： Shaffer, AL Yu, X He, YS Boldrick, J Chan, EP Staudt, LM NCI Metab Branch Div Clin Sci Bethesda MD 20892 USA

BCL-6, a transcriptional repressor frequently translocated in lymphomas, regulates germinal center B cell differentiation and inflammation. DNA microarray screening identified genes repressed by BCL-6, including many lymphocyte activation genes, suggesting that BCL-6 modulates B cell receptor signals. BCL-6 repression of two chemokine genes, MIP-1 alpha and IP-10, may also attenuate inflammatory responses. Blimp-1, another BCL-6 target, is important for plasmacytic differentiation. Since BCL-6 expression is silenced in plasma cells, repression of blimp-1 by BCL-6 may control plasmacytic differentiation. Indeed, inhibition of BCL-6 function initiated changes indicative of plasmacytic differentiation, including decreased expression of c-Myc and increased expression of the cell cycle inhibitor p27kip1. These data suggest that malignant transformation by BCL-6 involves inhibition of differentiation and enhanced proliferation.

关键词： B淋巴细胞/细胞学 B淋巴细胞/生理学细胞周期/遗传学细胞分化/遗传学细胞培养的 DNA结合蛋白质类/遗传学基因表达调控炎症/遗传学原癌基因蛋白质类/遗传学原癌基因蛋白质c-bcl-6 信号传导/遗传学转录因子/遗传学转录遗传动物小鼠

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Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner

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MOLECULAR AND CELLULAR BIOLOGY 2000年第5期20卷 1713-1722页

作者： Potapova, O Gorospe, M Dougherty, RH Dean, NM Gaarde, WA Holbrook, NJ NIA Cell Stress & Aging Sect Biol Chem Lab GRCNIH Baltimore MD 21224 USA ISIS Pharmaceut Carlsbad CA 92008 USA

c-Jun N-terminal kinase (JNK) plays a critical role in coordinating the cellular response to stress and has been implicated in regulating cell growth and transformation. To investigate the growth-regulatory functions of JNK1 and JNK2, we used specific antisense oligonucleotides (AS) to inhibit their expression. A survey of several human tumor cell lines revealed that JNKAS treatment markedly inhibited the growth of cells with mutant p53 status but not that of cells with normal p53 function, To further examine the influence of p53 on cell sensitivity to JNKAS treatment, we compared the responsiveness of RKO, MCF-7, and HCT116 cells with normal p53 function to that of RKO E6, MCF-7 E6, and HCT116 p53(-/-), which were rendered p53 deficient by different methods. Inhibition of JNK2 (and to a lesser extent JNK1) expression dramatically reduced the growth of p53-deficient cells but not that of their normal counterparts. JNK2AS-induced growth inhibition was correlated with significant apoptosis, JNK2AS treatment induced the expression of the cyclin-dependent kinase inhibitor p21(Cip1/Waf1) in parental MCF-7, RKO, and HCT116 cells but not in the p53-deficient derivatives. That p21(Cip1/Waf1) expression contributes to the survival of JNK2AS-treated cells was supported by additional experiments demonstrating that p21(Cip1/Waf1) deficiency in HCT116 cells also results in heightened sensitivity to JNKAS treatment. Our results indicate that perturbation of JNK2 expression adversely affects the growth of otherwise nonstressed cells, p53 and its downstream effector p21(Cip1/Waf1) important in counteracting these detrimental effects and promoting cell survival.

关键词：细胞凋亡/遗传学细胞分裂/遗传学细胞存活/遗传学基因表达调控酶学基因表达调控肿瘤丝裂原活化蛋白激酶9 丝裂原激活蛋白激酶类蛋白激酶类/生物合成蛋白激酶类/遗传学信号传导/遗传学肿瘤细胞培养的肿瘤抑制蛋白质p53/遗传学肿瘤抑制蛋白质p53/代谢女(雌)性人类

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