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CUG连接蛋白1基因在前列腺癌的表达及其功能研究  [PDF]
段宝民,逯锦涛,王卫民,李 兵,牛保华
重庆医科大学学报 , 2012,
Abstract: 目的:探讨CUG连接蛋白1(CUG-BindingProtein1,CUGBP1)基因在前列腺癌的表达及其蛋白功能。方法:用定量RT-PCR法在前列腺癌组织和癌旁组织中检测CUGBP的mRNA水平。Westernblot法检测4种前列腺癌细胞株(22RV1,PC-3,DU145,LNCaPcloneFGC)中CUGBP1的表达。利用RNA干扰技术检测PC-3细胞在CUGBP1基因沉默后细胞的增殖与凋亡状态。利用定量RT-PCR法确定其下游调控基因的mRNA水平。结果:CUGBP1在PC-3和22RV1细胞株中高表达。CUGBP1的mRNA在前列腺癌组织中较癌旁组织显著增高。CUGBP1基因shRNA导致CUGBP1基因沉默后抑制了PC-3细胞株的增殖并诱导其凋亡;同时,使前列腺癌细胞在细胞周期上发生G1期阻滞。CUGBP1基因被干扰以后,PC-3细胞株中CDKN1A的mRNA水平发生明显上调,同时BCL2、PCNA、MCM2和MCM3基因的mRNA水平发生明显下调。结论:CUGBP1基因和前列腺癌相关。CUGBP1基因可能通过上调/下调下游基因来调节前列腺癌细胞的凋亡,改变细胞的增殖和细胞周期。
CUG连接蛋白1在胃癌组织中的表达及对SGC7901细胞增殖和侵袭能力的影响
Expression of CUG-binding protein 1 in gastric cancer tissue and its effect on SGC7901 cell proliferation and invasion
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,,桂芬芳,罗子华,吴京华,黎发明,郑建伟
- , 2018, DOI: 10.13705/j.issn.1671-6825.2018.01.014
Abstract: 目的:探讨CUG连接蛋白1(CUGBP1)在胃癌组织中的表达及对SGC7901细胞增殖和侵袭能力的影响。方法: 收集82例胃癌和癌旁正常组织,免疫组化法检测CUGBP1蛋白。将人胃癌SGC7901细胞分为CUGBP1 siRNA组、对照siRNA组和空白对照组。转染48 h后,实时荧光定量PCR法检测细胞中CUGBP1 mRNA,MTT法检测细胞增殖能力,划痕实验检测细胞迁移能力,Transwell法检测细胞迁移和侵袭能力。结果:胃癌组织中CUGBP1蛋白阳性表达率为76.8%,高于癌旁正常组织(47.6%)(P<0.05); 胃癌组织中CUGBP1蛋白阳性表达与分化程度、TNM分期、浸润深度和淋巴结转移有关(P<0.05)。与两个对照组比较,CUGBP1 siRNA组细胞中CUGBP1 mRNA相对表达量、划痕修复率降低,迁移细胞数和侵袭细胞数减少(P<0.05)。结论:CUGBP1蛋白与胃癌的发生发展关系密切。
Aim: To investigate the expression of CUG-binding protein 1(CUGBP1 )in gastric cancer and its effect on cell proliferation and invasion.Methods: A total of 82 cases of gastric cancer and paracancerous tissue were selected,immunohistochemistry was used to detect the expression of CUGBP1. Human gastric cancer SGC7901 cells were divided into CUGBP1 siRNA group,control siRNA group and blank control group. After 48 h transfection, real-time fluorescence quantitative PCR was used to detect the expression of CUGBP1 mRNA in cells, MTT assay was used to detect cell proliferation, scratch test was used to detect cell migration ability, Transwell assay was used to detect cell migration and invasion.Results: The positive rate of CUGBP1 protein in gastric cancer tissue was 76.8%,which was higher than that(47.6%)in normal tissue(P<0.05). The positive rate of CUGBP1 in gastric cancer tissue was related to the degree of differentiation,TNM stage,depth of invasion and lymph node metastasis(P<0.05). Compared with those of control siRNA group and blank control group, the relative expression level of CUGBP1 mRNA in CUGBP siRNA group was lower, the wound healing rates, the number of migrating cells and the number of invasive cells were significantly reduced(P<0.05).Conclusion: CUGBP1 protein is related to the carcinogenesis and development of gastric cancer
Free-ordered CUG on Chemical Abstract Machine  [PDF]
Satoshi Tojo
Computer Science , 1994,
Abstract: We propose a paradigm for concurrent natural language generation. In order to represent grammar rules distributively, we adopt categorial unification grammar (CUG) where each category owns its functional type. We augment typed lambda calculus with several new combinators, to make the order of lambda-conversions free for partial / local processing. The concurrent calculus is modeled with Chemical Abstract Machine. We show an example of a Japanese causative auxiliary verb that requires a drastic rearrangement of case domination.
Unanticipated Antigens: Translation Initiation at CUG with Leucine  [PDF]
Susan R. Schwab,Jessica A. Shugart,Tiffany Horng,Subramaniam Malarkannan,Nilabh Shastri
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020366
Abstract: Major histocompatibility class I molecules display tens of thousands of peptides on the cell surface for immune surveillance by T cells. The peptide repertoire represents virtually all cellular translation products, and can thus reveal a foreign presence inside the cell. These peptides are derived from not only conventional but also cryptic translational reading frames, including some without conventional AUG codons. To define the mechanism that generates these cryptic peptides, we used T cells as probes to analyze the peptides generated in transfected cells. We found that when CUG acts as an alternate initiation codon, it can be decoded as leucine rather than the expected methionine residue. The leucine start does not depend on an internal ribosome entry site–like mRNA structure, and its efficiency is enhanced by the Kozak nucleotide context. Furthermore, ribosomes scan 5′ to 3′ specifically for the CUG initiation codon in a eukaryotic translation initiation factor 2–independent manner. Because eukaryotic translation initiation factor 2 is frequently targeted to inhibit protein synthesis, this novel translation mechanism allows stressed cells to display antigenic peptides. This initiation mechanism could also be used at non-AUG initiation codons often found in viral transcripts as well as in a growing list of cellular genes.
Unanticipated Antigens: Translation Initiation at CUG with Leucine  [PDF]
Susan R Schwab,Jessica A Shugart,Tiffany Horng,Subramaniam Malarkannan,Nilabh Shastri
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020366
Abstract: Major histocompatibility class I molecules display tens of thousands of peptides on the cell surface for immune surveillance by T cells. The peptide repertoire represents virtually all cellular translation products, and can thus reveal a foreign presence inside the cell. These peptides are derived from not only conventional but also cryptic translational reading frames, including some without conventional AUG codons. To define the mechanism that generates these cryptic peptides, we used T cells as probes to analyze the peptides generated in transfected cells. We found that when CUG acts as an alternate initiation codon, it can be decoded as leucine rather than the expected methionine residue. The leucine start does not depend on an internal ribosome entry site–like mRNA structure, and its efficiency is enhanced by the Kozak nucleotide context. Furthermore, ribosomes scan 5′ to 3′ specifically for the CUG initiation codon in a eukaryotic translation initiation factor 2–independent manner. Because eukaryotic translation initiation factor 2 is frequently targeted to inhibit protein synthesis, this novel translation mechanism allows stressed cells to display antigenic peptides. This initiation mechanism could also be used at non-AUG initiation codons often found in viral transcripts as well as in a growing list of cellular genes.
Genetic and Chemical Modifiers of a CUG Toxicity Model in Drosophila  [PDF]
Amparo Garcia-Lopez, Lidon Monferrer, Irma Garcia-Alcover, Marta Vicente-Crespo, M. Carmen Alvarez-Abril, Ruben D. Artero
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001595
Abstract: Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments.
Cug2 is essential for normal mitotic control and CNS development in zebrafish
Hyun-Taek Kim, Ju-Hoon So, Seung-Hyun Jung, Dae-Gwon Ahn, Wansoo Koh, Nam-Soon Kim, Soo-Hyun Kim, Soojin Lee, Cheol-Hee Kim
BMC Developmental Biology , 2011, DOI: 10.1186/1471-213x-11-49
Abstract: To study the function of CUG2 in vivo, we isolated a zebrafish homologue that is expressed specifically in the proliferating cells of the central nervous system (CNS). Morpholino-mediated knockdown of cug2 resulted in apoptosis throughout the CNS and the development of neurodegenerative phenotypes. In addition, cug2-deficient embryos contained mitotically arrested cells displaying abnormal spindle formation and chromosome misalignment in the neural plate.Therefore, our findings suggest that Cug2 is required for normal mitosis during early neurogenesis and has functions in neuronal cell maintenance, thus demonstrating that the cug2 deficient embryos may provide a model system for human neurodegenerative disorders.Cancer-upregulated gene 2 (CUG2) is known to be differentially expressed in multiple human cancer tissues including the ovary, liver, lung, intestines and pancreas [1]. Mammalian cells overexpressing CUG2 showed hallmarks of neoplasmic transformation in vitro, such as increased cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in nude mice, similar to the effects of the H-ras oncogene [1].Recently, CUG2 was shown to interact with CENP-T and CENP-A, essential components of the nucleosome complex located at the centromere, and was hence named centromere protein W (CENP-W) [2,3]. The centromere is involved in sister chromatid cohesion and the attachment of spindle microtubules, and is thus responsible for accurate chromosome segregation during mitotic and meiotic cell division [4]. CENP-A, a histone H3-like core protein, is required for the recruitment of many constitutive centromere components as well as transient kinetochore components [5,6]. We and others have reported that CUG2/CENP-W forms a DNA-binding complex together with the CENP-T and CENP-A as part of the centromere chromatin structure [2,3]. SiRNA-mediated knockdown of CUG2/CENP-W in HeLa cells caused defective mitosis characterized by multipolar spindle forma
Cytoplasmic CUG RNA Foci Are Insufficient to Elicit Key DM1 Features  [PDF]
Warunee Dansithong, Cordula M. Wolf, Partha Sarkar, Sharan Paul, Andy Chiang, Ian Holt, Glenn E. Morris, Dorothy Branco, Megan C. Sherwood, Lucio Comai, Charles I. Berul, Sita Reddy
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003968
Abstract: The genetic basis of myotonic dystrophy type I (DM1) is the expansion of a CTG tract located in the 3′ untranslated region of DMPK. Expression of mutant RNAs encoding expanded CUG repeats plays a central role in the development of cardiac disease in DM1. Expanded CUG tracts form both nuclear and cytoplasmic aggregates, yet the relative significance of such aggregates in eliciting DM1 pathology is unclear. To test the pathophysiology of CUG repeat encoding RNAs, we developed and analyzed mice with cardiac-specific expression of a beta-galactosidase cassette in which a (CTG)400 repeat tract was positioned 3′ of the termination codon and 5′ of the bovine growth hormone polyadenylation signal. In these animals CUG aggregates form exclusively in the cytoplasm of cardiac cells. A key pathological consequence of expanded CUG repeat RNA expression in DM1 is aberrant RNA splicing. Abnormal splicing results from the functional inactivation of MBNL1, which is hypothesized to occur due to MBNL1 sequestration in CUG foci or from elevated levels of CUG-BP1. We therefore tested the ability of cytoplasmic CUG foci to elicit these changes. Aggregation of CUG RNAs within the cytoplasm results both in Mbnl1 sequestration and in approximately a two fold increase in both nuclear and cytoplasmic Cug-bp1 levels. Significantly, despite these changes RNA splice defects were not observed and functional analysis revealed only subtle cardiac dysfunction, characterized by conduction defects that primarily manifest under anesthesia. Using a human myoblast culture system we show that this transgene, when expressed at similar levels to a second transgene, which encodes expanded CTG tracts and facilitates both nuclear focus formation and aberrant splicing, does not elicit aberrant splicing. Thus the lack of toxicity of cytoplasmic CUG foci does not appear to be a consequence of low expression levels. Our results therefore demonstrate that the cellular location of CUG RNA aggregates is an important variable that influences toxicity and support the hypothesis that small molecules that increase the rate of transport of the mutant DMPK RNA from the nucleus into the cytoplasm may significantly improve DM1 pathology.
Overexpression of CUGBP1 in Skeletal Muscle from Adult Classic Myotonic Dystrophy Type 1 but Not from Myotonic Dystrophy Type 2  [PDF]
Rosanna Cardani, Enrico Bugiardini, Laura V. Renna, Giulia Rossi, Graziano Colombo, Rea Valaperta, Giuseppe Novelli, Annalisa Botta, Giovanni Meola
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083777
Abstract: Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.
p21WAF1/CIP1 Upregulation through the Stress Granule-Associated Protein CUGBP1 Confers Resistance to Bortezomib-Mediated Apoptosis  [PDF]
Cristina Gareau, Marie-Josée Fournier, Christine Filion, Laetitia Coudert, David Martel, Yves Labelle, Rachid Mazroui
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020254
Abstract: Background p21WAF1/CIP1 is a well known cyclin-dependent kinase inhibitor induced by various stress stimuli. Depending on the stress applied, p21 upregulation can either promote apoptosis or prevent against apoptotic injury. The stress-mediated induction of p21 involves not only its transcriptional activation but also its posttranscriptional regulation, mainly through stabilization of p21 mRNA levels. We have previously reported that the proteasome inhibitor MG132 induces the stabilization of p21 mRNA, which correlates with the formation of cytoplasmic RNA stress granules. The mechanism underlying p21 mRNA stabilization, however, remains unknown. Methodology/Principal Findings We identified the stress granules component CUGBP1 as a factor required for p21 mRNA stabilization following treatment with bortezomib ( = PS-341/Velcade). This peptide boronate inhibitor of the 26S proteasome is very efficient for the treatment of myelomas and other hematological tumors. However, solid tumors are sometimes refractory to bortezomib treatment. We found that depleting CUGBP1 in cancer cells prevents bortezomib-mediated p21 upregulation. FISH experiments combined to mRNA stability assays show that this effect is largely due to a mistargeting of p21 mRNA in stress granules leading to its degradation. Altering the expression of p21 itself, either by depleting CUGBP1 or p21, promotes bortezomib-mediated apoptosis. Conclusions/Significance We propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1.
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