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Human telomerase activation requires two independent interactions between telomerase RNA and telomerase reverse transcriptase

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MOLECULAR CELL 2000年第2期6卷 361-371页

作者： Mitchell, JR Collins, K Univ Calif Berkeley Dept Mol & Cell Biol Div Biochem & Mol Biol Berkeley CA 94720 USA

Inhibition or activation of the reverse transcriptase telomerase can profoundly affect the proliferative capacity of normal cells and cancers. Here, we elucidate structural requirements for function of the essential RNA component of human telomerase, hTR. Two motifs within the independently stable H/ACA domain of hTR are required for accumulation of the mature RNA in vivo. However, these motifs can be substituted by a heterologous H/ACA family RNA. Two additional hTR elements are required both in vivo and in vitro for telomerase catalytic activity. Surprisingly, each of these elements independently binds to the telomerase reverse transcriptase. Our results establish fundamental differences between vertebrate and ciliate telomerase ribonucleoprotein architectures and also suggest strategies for the pharmaceutical development of telomerase-based anticancer therapies.

关键词：碱基序列催化域细胞周期蛋白质类/代谢细胞系 DNA结合蛋白质类酶激活分子序列数据核蛋白质类/代谢核酸构象 RNA/化学 RNA/代谢重组融合蛋白质类/代谢末端转移酶端粒/化学末端转移酶端粒/代谢转染人类

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The COOH-terminal transactivation domain plays a key role in regulating the in vitro and in vivo function of Pax3 homeodomain

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第13期275卷 9854-9862页

作者： Cao, Y Wang, CY Univ Illinois Ctr Mol Biol Oral Dis Chicago IL 60612 USA

Efficient transcription activation by Pax3 requires binding to a complex DNA sequence element containing binding sites for both the paired domain and the Prd type homeodomain. Previously, we have shown that this requirement is lost in PAX3-FKHR, the product of a t(2;13) chromosomal translocation associated with alveolar rhabdomyosarcoma. In contrast to Pax3, the chimeric PAX3-FKHR, which acts as an oncogene, can efficiently activate a DNA sequence element containing only a homeodomain binding site (TAATAN(2-3)ATTA), de spite the presence of an intact Pax3 paired domain, Here, we showed that this alteration in sequence-specific transcription activity was determined in part by the transactivation domain. First, we demonstrated that in intact Pax3, substitution of the Pax3 transactivation domain with an unrelated viral VP16 transactivation domain enabled Pax3 to transactivate homeodomain-specific DNA sequence, as well as to transform fibroblasts. Furthermore, we could abolish the homeodomain-dependent transcription and transforming activities of PAX3-FKHR by replacing its FKHR transactivation domain with Pax3 transactivation domain. Collectively, these results suggested that the transactivation domain influences the DNA binding specificity of Pax3. The translocation process increased the oncogenic potential of Pax3 by removing the inhibitory action of Pax3 transactivation domain on its homeodomain.

关键词： 3T3细胞碱基序列 DNA DNA引物 DNA结合蛋白质类/代谢 DNA结合蛋白质类/生理学叉头转录因子类同源盒结构域蛋白质类/代谢同源盒结构域蛋白质类/生理学核蛋白质类/代谢成对盒转录因子类重组融合蛋白质类/代谢转录因子/代谢转录因子/生理学转录激活肿瘤细胞培养的动物小鼠

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Progesterone stimulation of human insulin-like growth factor-binding protein-5 gene transcription in human osteoblasts is mediated by a CACCC sequence in the proximal promoter

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第37期274卷 26431-26438页

作者： Boonyaratanakornkit, V Strong, DD Mohan, S Baylink, DJ Beck, CA Linkhart, TA Loma Linda Univ JL Pettis VAMC Musculoskeletal Dis Ctr Res Serv 151 Loma Linda CA 92357 USA Loma Linda Univ Dept Biochem Loma Linda CA 92357 USA Loma Linda Univ Dept Microbiol & Mol Genet Loma Linda CA 92357 USA Loma Linda Univ Dept Pediat Loma Linda CA 92357 USA Loma Linda Univ Dept Physiol Loma Linda CA 92357 USA Loma Linda Univ Dept Med Loma Linda CA 92357 USA Univ Colorado Hlth Sci Ctr Dept Pathol Denver CO 80262 USA

Insulin-like growth factor-binding protein-5 (IGFBP-5) is produced by osteoblasts and potentiates insulin-like growth factor mitogenic stimulation in osteoblast cell. cultures. Progesterone (PG) increased IGFBP-5 expression in normal human osteoblasts and increased IGEBP-5 transcription in U2 human osteosarcoma cells. We developed a chloramphenicol acetyltransferase reporter construct containing the human IGFBP-5 proximal promoter sequence, which includes TATA and CAAT boxes, and five putative PG response element half-sites. 10(-8) M PG increased promoter activity of this construct in U2 cells co-transfected with a PG receptor isoform A (PRA) expression vector. Analysis of 5' deletion constructs indicates that PG transactivation of IGFBP-5 promoter activity does not require the PG response element half-sites but does require the region -162 to -124 containing two tandem CACCC box sequences. Mutation of the proximal CACCC box at -139 eliminated PG transactivation. Gel shift assays using a -162 to -124 DNA fragment, U2 cell nuclear extracts, and purified PRA protein indicate that nuclear factors bind to a CACCC sequence at -139 and that PRA alters the pattern of transcription factor interaction with the CACCC sequence. Using a luciferase reporter construct containing base pairs -252 to +24 of the IGFBP-5 promoter, we found that both PRA and PRB isoforms mediated PG stimulation of promoter activity. These results suggest that PG may stimulate IGFBP-5 gene transcription via a novel mechanism involving PR and CACCC-binding factors.

关键词：碱基序列 DNA引物激素拮抗药/药理学胰岛素样生长因子结合蛋白质5/遗传学米非司酮/药理学核蛋白质类/代谢成骨细胞/药物作用成骨细胞/代谢孕酮/药理学启动区遗传转录遗传/药物作用肿瘤细胞培养的人类

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Coregulator small nuclear RING finger protein (SNURF) enhances Sp1-and steroid receptor-mediated transcription by different mechanisms

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第1期275卷 571-579页

作者： Poukka, H Aarnisalo, P Santti, H Jänne, OA Palvimo, JJ Univ Helsinki Inst Biomed Dept Physiol FIN-00014 Helsinki Finland Univ Helsinki Dept Clin Chem FIN-00014 Helsinki Finland

The small nuclear RING finger protein SNURF is not only a coactivator in steroid receptor-dependent transcription but also activates transcription from steroid-independent promoters. In this work, we show that SNURF, via the RING finger domain, enhances protein binding to Sp1 elements/GC boxes and interacts and cooperates with Sp1 in transcriptional activation. The activation of androgen receptor (AR) function requires regions other than the RING finger of SNURF, and SNURF does not influence binding of AR to cognate DNA elements. The zinc finger region (ZFR) together with the hinge region of AR are sufficient for contacting SNURF. The nuclear localization signal in the boundary between ZFR and the hinge region participates in the association of AR with SNURF, and a receptor mutant lacking the C-terminal part of the bipartite nuclear localization signal shows attenuated response to coexpressed SNURF. Some AR ZFR point mutations observed in patients with partial androgen insensitivity syndrome or male breast cancer impair the interaction of AR with SNURF and also render AR refractory to the transcription-activating effect of SNURF. Collectively, SNURF modulates the transcriptional activities of androgen receptor and Sp1 via different domains, and it may act as a functional link between steroid- and Sp1-regulated transcription.

关键词：氨基酸序列雄激素迟钝综合征/遗传学乳腺肿瘤男性/遗传学 DNA结合蛋白质类/代谢基因表达调控分子序列数据核定位信号核蛋白质类/遗传学核蛋白质类/代谢点突变启动区遗传蛋白质结合受体雄激素/代谢重组蛋白质类/代谢 Sp1转录因子/代谢转录因子/遗传学转录因子/代谢转录遗传锌指/遗传学人类男(雄)性

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Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第26期274卷 18463-18469页

作者： Tsukamoto, N Hattori, M Yang, HL Bos, JL Minato, N Kyoto Univ Grad Sch Med Dept Immunol & Cell Biol Kyoto 6068501 Japan Univ Utrecht Physiol Chem Lab NL-2584 CG Utrecht Netherlands

Rap1 GTPase is activated by a variety of stimulations in many types of cells, but its exact functions remain unknown. In this study we have shown that SPA-1 interferes with Rap1 activation by membrane-targeted C3G, C3G-F, in 293T cells through the GTPase activating protein (GAP) activity. SPA-1 transiently expressed in HeLa cells was mostly localized at the cortical cytoskeleton and induced rounding up of the cells, whereas C3G-F conversely induced extensive cell spreading. Conditional SPA-1 overexpression in HeLa cells by tetracycline-regulative system suppressed Rap1 activation upon plating on dishes coated with fibronectin and resulted in the reduced adhesion. When SPA-1 was conditionally induced after the established cell adhesion, the cells gradually rounded up and detached from the dish. Both effects were counteracted by exogenous fibronectin in a dose-dependent manner. Retroviral overexpression of SPA-1 in promyelocytic 32D cells also inhibited both activation of Rap1 and induction of cell adhesion by granulocyte colony stimulating factor without affecting differentiation. These results have indicated that Rap1 GTP is required for the cell adhesion induced by both extracellular matrix and soluble factors, which is negatively regulated by SPA-1.

关键词：细胞黏附/药物作用细胞黏附/生理学细胞分化/药物作用纤连蛋白类/药理学 GTP结合蛋白质类/代谢 GTP酶激活蛋白质类基因肿瘤抑制粒细胞集落刺激因子/药理学 HeLa细胞核蛋白质类/代谢核蛋白质类/生理学原癌基因蛋白质类/代谢逆转录病毒科转录因子/代谢转染 rapGTP结合蛋白质类动物人类兔

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Splitting the chromosome: Cutting the ties that bind sister chromatids

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SCIENCE 2000年第5470期288卷 1379-1384页

作者： Nasmyth, K Peters, LM Uhlmann, F Res Inst Mol Pathol A-1030 Vienna Austria

In eukaryotic cells, sister DNA molecules remain physically connected from their production at S phase until their separation during anaphase. This cohesion is essential for the separation of sister chromatids to opposite poles of the cell at mitosis. It also permits chromosome segregation to take place long after duplication has been completed. Recent work has identified a multisubunit complex called cohesin that is essential for connecting sisters. Proteolytic cleavage of one of cohesin's subunits may trigger sister separation at the onset of anaphase,

关键词：后期细胞周期蛋白质类/代谢染色单体/代谢染色体蛋白质类非组蛋白染色体分离内肽酶类真菌蛋白质类异染色质/化学异染色质/代谢连接酶类/代谢中期核蛋白质类/化学核蛋白质类/代谢泛素蛋白连接酶复合物泛素蛋白连接酶类动物人类

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Regulation of phosphatidylcholine metabolism in Chinese hamster ovary cells by the sterol regulatory element-binding protein (SREBP)/SREBP cleavage-activating protein pathway

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第19期275卷 14367-14374页

作者： Lagace, TK Storey, MK Ridgway, ND Dalhousie Univ Clin Res Ctr Atlantic Res Ctr Halifax NS B3H 4H7 Canada Dalhousie Univ Dept Pediat Halifax NS B3H 4H7 Canada Dalhousie Univ Dept Biochem Halifax NS B3H 4H7 Canada Dalhousie Univ Dept Mol Biol Halifax NS B3H 4H7 Canada

Sterol regulation-defective (SRD) 4 cells expressing a mutant sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP D443N) and Chinese hamster ovary (CHO) cells stably expressing SCAS (CHO-SCAP) and SCAP D443N (CHO-SCAP-D443N) have increased cholesterol and fatty acid synthesis because of constitutive processing of SREBPs, We assessed whether constitutive activation of SREBPs also influenced the CDP-choline pathway for phosphatidylcholine (PtdCho) biosynthesis. Relative to control CHO 7 cells, SRD 4 cells displayed increased PtdCho synthesis and degradation as indicated by a 4-6-fold increase in [H-3]choline incorporation into PtdCho and 10-15-fold increase in intracellular [H-3]glycerophosphocholine. [H-3]Phosphocholine levels in SRD 4 cells were reduced by over 10-fold, suggesting enhanced activity of CTP:phosphocholine cytidylyltransferase alpha (CCT alpha). CHO-SCAP and CHO-SCAP D443N cells displayed modest increases in [H-3]choline incorporation into PtdCho (2-fold) and only a 2-fold reduction in [H-3]phosphocholine. Elevated PtdCho metabolism in SRD 4, compared with SCAP-overexpressing cells, was correlated with fatty acid synthesis. Inhibition of fatty acid synthesis by cerulenin resulted in almost complete normalization of PtdCho synthesis and choline metabolite profiles in SRD 4 cells, indicating that fatty acids or a fatty acid-derived metabolite was responsible for up-regulation of PtdCho synthesis. In contrast to apparent activation in vivo, CCT alpha protein, mRNA, and in vitro activity were reduced in SRD 4 cells and unchanged in SCAR transfected cells. Unlike control and SCAP transfected cells, CCT alpha in SRD 4 cells was localized by immunofluorescence to the nuclear envelope, suggesting that residual enzyme activity in these cells was in an active membrane-associated form. Translocation of CCT alpha to the nuclear envelope was reproduced by treatment of CHO 7 cells with exogenous oleate, We conclude that the SREBP/SCAP

关键词： CCAAT增强子结合蛋白类 CHO细胞胆碱磷酸胞苷酰转移酶/遗传学仓鼠亚科仓鼠属 DNA结合蛋白质类/代谢二酰甘油胆碱磷酸转移酶/遗传学 HeLa细胞水解作用细胞内信号肽和蛋白质类膜蛋白质类/遗传学膜蛋白质类/代谢核蛋白质类/代谢磷脂酰胆碱类/代谢 RNA 信使/遗传学 RNA 信使/代谢胆固醇调节元件结合蛋白质1 转录因子转染动物人类

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Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第41期275卷 32310-32316页

作者： Gross, C Kelleher, M Iyer, VR Brown, PO Winge, DR Univ Utah Hlth Sci Ctr Dept Med Salt Lake City UT 84132 USA Univ Utah Hlth Sci Ctr Dept Biochem Salt Lake City UT 84132 USA Stanford Univ Sch Med Dept Biochem Howard Hughes Med Inst Stanford CA 94305 USA

In Saccharomyces cerevisiae, copper ions regulate gene expression through the two transcriptional activators, Ace1 and Mad. Ace1 mediates copper-induced gene expression in cells exposed to stressful levels of copper salts, whereas Mad activates a subset of genes under copper-deficient conditions. DNA microarray hybridization experiments revealed a limited set of yeast genes differentially expressed under growth conditions of excess copper or copper deficiency. Mad activates the expression of six S. cerevisiae genes, including CTR1, CTR3, FRE1, FRE7, YFR055w, and YJL217w, Two of the last three newly identified Mad target genes have no known function;the third, YFR055w, is homologous to cystathionine gamma-lyase encoded by CYS3. Several genes that are differentially expressed in cells containing a constitutively active Mad, designated Mac1(up1), are not direct targets of Mad. Induction or repression of these genes is likely a secondary effect of cells because of constitutive Mad activity. Elevated copper levels induced the expression of the metallothioneins CUP1 and CRS5 and two genes, FET3 and FTR1, in the iron uptake system. Copper-induced FET3 and FTR1 expression arises from an indirect copper effect on cellular iron pools.

关键词：曲霉核酸酶S1/代谢载体蛋白质类铜/缺乏铜/代谢铜/药理学 DNA结合蛋白质类/代谢减量调节/药物作用真菌蛋白质类/遗传学真菌蛋白质类/代谢基因表达谱基因表达调控真菌/药物作用基因真菌/遗传学铁/代谢金属硫蛋白/遗传学金属硫蛋白/代谢核蛋白质类/代谢核酸酶保护测定寡核苷酸序列分析 RNA 信使/遗传学 RNA 信使/代谢酵母菌酿酒/药物作用酵母菌酿酒/遗传学酵母菌酿酒/代谢酿酒酵母蛋白质类转录因子/代谢增量调节/药物作用

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Conditional expression of fibroblast growth factor-7 in the developing and mature lung

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第16期275卷 11858-11864页

作者： Tichelaar, JW Lu, W Whitsett, JK Childrens Hosp Med Ctr Div Pulm Biol Cincinnati OH 45229 USA

Effects of fibroblast growth factor-7 (FGF-7) on lung morphogenesis, respiratory epithelial cell differentiation, and proliferation mere assessed in transgenic mice in which the human FGF-7 cDNA was controlled by a conditional promoter under the direction of regulatory elements from either the human surfactant protein-C (SP-C) or rat Clara cell secretory protein (ccsp) genes. Expression of FGF-7 was induced in respiratory epithelial cells of the fetal lung by administration of doxycycline to the dam. Prenatally, doxycycline induced FGF-7 mRNA in respiratory epithelial cells in both Sp-c and Ccsp transgenic lines, increasing lung size and causing cystadenomatoid malformation. Postnatally, mice bearing both Ccsp-rtta and (Teto)(7)-cmv-fgf-7 transgenes survived, and lung morphology was normal, Induction of FGF-7 expression by doxycycline in the Ccsp-rtta x (Teto)(7)-cmv-fgf-7 mice caused marked epithelial cell proliferation, adenomatous hyperplasia, and pulmonary infiltration with mononuclear cells. Epithelial cell hyperplasia caused by FGF-7 was largely resolved after removal of doxycycline. Surfactant proteins, TTF-1, and aquaporin 5 expression were conditionally induced by doxycycline. The Sp-c-rtta and Ccsp-rtta activator mice provide models in which expression is conditionally controlled in respiratory epithelial cells in the developing and mature lung, altering lung morphogenesis, differentiation, and proliferation.

关键词：水通道蛋白质5 水孔蛋白质类/代谢多西环素/药理学酶抑制剂/代谢上皮细胞/代谢成纤维细胞生长因子10 成纤维细胞生长因子7 成纤维细胞生长因子基因表达调控发育期生长物质/生物合成生长物质/遗传学原位杂交肺/生长和发育膜蛋白质类小鼠转基因核蛋白质类/代谢磷脂酶A/拮抗剂和抑制剂蛋白质类/遗传学蛋白质类/代谢蛋白脂质类/遗传学蛋白脂质类/代谢肺表面活性剂/遗传学肺表面活性剂/代谢转录因子/代谢转基因子宫珠蛋白/代谢动物人类小鼠大鼠

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Transcriptional regulation of the murine surfactant protein-A gene by B-myb

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第39期274卷 27523-27528页

作者： Bruno, MD Whitsett, JA Ross, GF Korfhagen, TR Childrens Hosp Res Fdn Div Pulm Biol Cincinnati OH 45229 USA

Surfactant protein A (SP-A) is selectively synthesized in subsets of cells lining the respiratory epithelium, where its expression is regulated by various transcription factors including thyroid transcription factor-1 (TTF-1), Cell-specific transcription of the mouse SP-A promoter is mediated by binding of TTF-1 at four distinct cis-active sites located in the 5'-flanking region of the gene, Mutation of TTF-1-binding sites (TBE) 1, 3, and 4 in combination markedly decreased transcriptional activity of SP-A promoter-chloramphenicol acetyltransferase constructs containing SP-A gene sequences from -256 to +45, In contrast, the same mutations enhanced transcriptional activity in constructs containing additional 5' SP-A sequences from -399 to +45 suggesting that cis-acting elements within the region -399 to -256 influence effects of TTF-1 on SP-A promoter activity. A consensus Myb-binding site was identified within the region, located at positions -380 to -371 in the mouse gene. Mutation of the Myb-binding site decreased activity of SP-A promoter constructs in MLE-15 cells. MLE-15 cells, a cell line expressing SP-A mRNA, also expressed B-Myb. B-Myb bound to the MBS in the SP-A gene as assessed by electrophoretic mobility shift assay. While co-transfection of HeLa cells with a E-Myb expression plasmid activated the transfected SP-A promoter about 3-fold, co-transfection of B-myb with cyclin A and cdk-2, to enhance phosphorylation of B-Myb, increased transcriptional activity of SP-A constructs approximately 20-fold. Taken together, the data support activation of SP-A gene promoter activity by E-Myb which acts at a cis-acting element in the SP-A gene.

关键词：碱基序列结合部位细胞周期蛋白质类细胞系细胞核/代谢共有序列 DNA结合蛋白质类/代谢基因表达调控糖蛋白类/遗传学 HeLa细胞分子序列数据诱变定点核蛋白质类/代谢癌基因蛋白质类/代谢启动区遗传蛋白脂质类/生物合成蛋白脂质类/遗传学肺表面活性物质相关蛋白质A 肺表面活性物质相关蛋白质类肺表面活性剂/生物合成肺表面活性剂/遗传学重组蛋白质类/生物合成调控序列核酸序列比对序列同源性核酸甲状腺/代谢反式激活因子类/代谢转录因子/代谢转录遗传转染动物人类小鼠大鼠

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