14 research outputs found
Mechanism mediated by a noncoding RNA, nc886, in the cytotoxicity of a DNA-reactive compound
DNA-reactive compounds are harnessed for cancer chemotherapy. Their genotoxic effects are considered to be the main mechanism for the cytotoxicity to date. Because this mechanism preferentially affects actively proliferating cells, it is postulated that the cytotoxicity is specific to cancer cells. Nonetheless, they do harm normal quiescent cells, suggesting that there are other cytotoxic mechanisms to be uncovered. By employing doxorubicin as a representative DNA-reactive compound, we have discovered a cytotoxic mechanism that involves a cellular noncoding RNA (ncRNA) nc886 and protein kinase R (PKR) that is a proapoptotic protein. nc886 is transcribed by RNA polymerase III (Pol III), binds to PKR, and prevents it from aberrant activation in most normal cells. We have shown here that doxorubicin evicts Pol III from DNA and, thereby, shuts down nc886 transcription. Consequently, the instantaneous depletion of nc886 provokes PKR and leads to apoptosis. In a short-pulse treatment of doxorubicin, these events are the main cause of cytotoxicity preceding the DNA damage response in a 3D culture system as well as the monolayer cultures. By identifying nc886 as a molecular signal for PKR to sense doxorubicin, we have provided an explanation for the conundrum why DNA-damaging drugs can be cytotoxic to quiescent cells that have the competent nc886/PKR pathway.ope
Transgenic overexpression of human LY6K in mice suppresses mature T cell development in the thymus
Lymphocyte antigen 6 family member K (LY6K) is upregulated in a number of types of cancer and promotes tumor cell proliferation and metastasis. In addition, LY6K is involved in tamoxifen resistance in breast cancer. However, the in vivo molecular mechanism of LY6K has not yet been investigated. In the present study, transgenic mice overexpressing human LY6K (hLY6K) were generated using the pMAMneo vector, and the effect of LY6K upregulation in vivo was investigated. A total of 4 transgenic mice were generated, and the gene copy number was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RT-qPCR demonstrated that mRNA of hLY6K was overexpressed in the thymus and spleen of the transgenic mice compared with wild-type mice. Flow cytometric analysis demonstrated that the proportions of B and T cells in the spleen were similar in wild-type and transgenic mice; however, the proportion of thymic mature T cells decreased in the transgenic mice, while there was an increase in the proportion of naΓ―ve T cells. These findings suggest that the overexpression of LY6K suppresses T cell development, and that LY6K is a potential therapeutic target for cancer.ope
Transcription factors Sp1 and Sp3 regulate expression of human ABCG2 gene and chemoresistance phenotype
ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by overexpression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.ope
Epigenome mapping highlights chromatin-mediated gene regulation in the protozoan parasite Trichomonas vaginalis
Trichomonas vaginalis is an extracellular flagellated protozoan parasite that causes trichomoniasis, one of the most common non-viral sexually transmitted diseases. To survive and to maintain infection, T. vaginalis adapts to a hostile host environment by regulating gene expression. However, the mechanisms of transcriptional regulation are poorly understood for this parasite. Histone modification has a marked effect on chromatin structure and directs the recruitment of transcriptional machinery, thereby regulating essential cellular processes. In this study, we aimed to outline modes of chromatin-mediated gene regulation in T. vaginalis. Inhibition of histone deacetylase (HDAC) alters global transcriptional responses and induces hyperacetylation of histones and hypermethylation of H3K4. Analysis of the genome of T. vaginalis revealed that a number of enzymes regulate histone modification, suggesting that epigenetic mechanisms are important to controlling gene expression in this organism. Additionally, we describe the genome-wide localization of two histone H3 modifications (H3K4me3 and H3K27Ac), which we found to be positively associated with active gene expression in both steady and dynamic transcriptional states. These results provide the first direct evidence that histone modifications play an essential role in transcriptional regulation of T. vaginalis, and may help guide future epigenetic research into therapeutic intervention strategies against this parasite.ope
Modulation of dendritic cell function by Trichomonas vaginalis-derived secretory products
Trichomoniasis caused by the parasitic protozoan Trichomonas vaginalis is the most common sexually transmitted disease in the world. Dendritic cells are antigen presenting cells that initiate immune responses by directing the activation and differentiation of naΓ―ve T cells. In this study, we analyzed the effect of Trichomonas vaginalis-derived Secretory Products on the differentiation and function of dendritic cells. Differentiation of bone marrow-derived dendritic cells in the presence of T. vaginalis-derived Secretory Products resulted in inhibition of lipopolysaccharide-induced maturation of dendritic cells, down-regulation of IL-12, and up-regulation of IL-10. The protein components of T. vaginalis-derived Secretory Products were shown to be responsible for altered function of bone marrow- derived dendritic cells. Chromatin immunoprecipitation assay demonstrated that IL-12 expression was regulated at the chromatin level in T. vaginalis-derived Secretory Productstreated dendritic cells. Our results demonstrated that T. vaginalis- derived Secretory Products modulate the maturation and cytokine production of dendritic cells leading to immune tolerance.ope
(The) role of PKMΞΆ in the nucleus accumbens in the expression of psychostimulantinduced locomotor sensitization
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A Study on Characterized Others through Isolated Fantasy : Based on My Works
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μΌλ‘ μ¬λ¬ λ§μ νλ κ²μ΄λ©°, κ³ μ λμ§ λͺ»νλ μ 체μ±μ κ³ μ λμ§ μμλ λ¨μ κ΄ν κ²μ΄λ€. κ·Έκ²μ νμμ λ΄λ‘ μμ κ·ΈμΉλ κ²μ΄ μλλΌ μ€λΈμ λ‘μμ νν, μμ κ³Ό μΆμ μ΄μκ°λ λ°©μκΉμ§ μ΄μ΄μ§λ€. μμ±λμ§ μμλ λλ μνκ³Ό κ·Έμ μ΄μ΄μ§λ μμ λ‘κ³ κ°λ²Όμ΄ μΆμ νλλ λμ μμ μμ μ€μν μ리λ₯Ό μ°¨μ§νκ³ μλ€.My art practice starts from realizing the social views of people. I have several methods for revealing this critical portion of their minds: being sarcastic, metaphoric, making pronouncements, crying, and staying calm. In the end, different ways are applied by any means. Moreover, by starting from conceptualizing others as characters, the narrative is built in my imagination of how they live and communicate. According to my imagination, a girl who pretends to be a monster and a monster who pretends to be a girl represent how people live and how society sees them, not by hiding their influence with a game or cartoon.
Then, different works based on these crooked people are collected into one character to be flexible and light, and my imaginary story about the illusion where they live continues. It is the world based on my imagination where everyone enjoys happiness and sadness as much as they want within a community. In this world, I look for peopleβs lives, clues about the meaning of existence, and a way that they can freely live.
This clue is about ambivalence, something about telling different things with different mouths, and how an identity that cannot be fixed does not have to be fixed. It is not finished with a discussion of others but continues with a painting as an object and as a way of art and life. An artwork that does not have to be finished and, in this respect, the free and light attitude of life takes an important position in my art practice.β
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Epigenetic regulation of RNA polymerase III transcription in early breast tumorigenesis
RNA polymerase III (Pol III) transcribes medium-sized non-coding RNAs (collectively termed Pol III genes). Emerging diverse roles of Pol III genes suggest that individual Pol III genes are exquisitely regulated by transcription and epigenetic factors. Here we report global Pol III expression/methylation profiles and molecular mechanisms of Pol III regulation that have not been as extensively studied, using nc886 as a representative Pol III gene. In a human mammary epithelial cell system that recapitulates early breast tumorigenesis, the fraction of actively transcribed Pol III genes increases reaching a plateau during immortalization. Hyper-methylation of Pol III genes inhibits Pol III binding to DNA via inducing repressed chromatin and is a determinant for the Pol III repertoire. When Pol III genes are hypo-methylated, MYC amplifies their transcription, regardless of its recognition DNA motif. Thus, Pol III expression during tumorigenesis is delineated by methylation and magnified by MYC.restrictio
Dynamic Long-Range Chromatin Interaction Controls Expression of IL-21 in CD4+ T Cells.
IL-21, a pleiotropic cytokine strongly linked with autoimmunity and inflammation, regulates diverse immune responses. IL-21 can be potently induced in CD4(+) T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il21 gene at the chromatin level. In this study, we demonstrated that a conserved noncoding sequence located 49 kb upstream of the Il21 gene contains an enhancer element that can upregulate Il21 gene expression in a STAT3- and NFAT-dependent manner. Additionally, we identified enhancer-blocking insulator elements in the Il21 locus, which constitutively bind CTCF and cohesin. In naive CD4(+) T cells, these upstream and downstream CTCF binding sites interact with each other to make a DNA loop; however, the Il21 promoter does not interact with any cis-elements in the Il21 locus. In contrast, stimulation of CD4(+) T cells with IL-6 leads to recruitment of STAT3 to the promoter and novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity. The long-range interaction between the promoter and distal enhancer region was dependent on IL-6/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of the Il21 gene.restrictio