Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nucleolus formation was studied as an indirect marker of the ribosomal RNA (rRNA) genes activation in porcine embryos following oocyte maturation, fertilization, and culture in vitro. Nucleologenesis was assessed by transmission electron microscopy (TEM), light microscopical autoradiography following 20 min of 3H-uridine incubation, and immunocytochemical localization of key nucleolar proteins involved in rRNA transcription (upstream binding factor (UBF), topoisomerase I, and RNA polymerase I) and processing (fibrillarin, nucleophosmin, nucleolin) by confocal laser scanning microscopy. During the first four post-fertilization cell cycles, TEM revealed spherical nucleolus precursor bodies (NPBs), consisting of densely packed fibrils, as the most prominent intra-nuclear entities of the blastomeres. Fibrillo-granular nucleoli were observed in some blastomeres in a single embryo during the 5th cell cycle, i.e., the tentative 16-cell stage, where formation of fibrillar centres (FC), a dense fibrillar component, and a granular component on the surface of the NPBs was seen. In this embryo, autoradiographic labeling was detected over the nucleoplasm and in particular over the nucleoli. Fibrillarin was immunocytochemically localized in the presumptive NPBs of the pronuclei. This protein was again localized to the presumptive NPBs together with nucleolin from late during the 3rd cell cycle, i.e., the four-cell stage in some embryos. UBF, RNA polymerase I, and nucleophosmin were localized to the presumptive NPBs in a proportion of the embryos at the 4th cell cycle, i.e., the tentative eight-cell stage and onwards. Toposiomerase I was not localized to intra-nuclear entities even during the 5th post-fertilization cell cycle. Moreover, a considerable proportion of the blastomere nuclei apparently did not show localization of other nucleolar proteins. In conclusion, porcine embryos produced in vitro display a substantial delay in or even lack of the development of functional nucleoli.
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PMID:Nucleolar ultrastructure and protein allocation in in vitro produced porcine embryos. 1511 26

The DNA damage-dependent poly(ADP-ribose) polymerases-1 and -2 (PARP-1 and PARP-2) are survival factors that share overlapping functions in the detection, signaling and repair of DNA strand breaks resulting from genotoxic lesions in mammalian cells. Here we show that PARP-1 and PARP-2 subnuclear distributions partially overlap, with both proteins accumulating within the nucleolus independently of each other. PARP-2 is enriched within the whole nucleolus and partially colocalizes with the nucleolar factor nucleophosmin/B23. We have identified a nuclear localization signal and a nucleolar localization signal within the N-terminal domain of PARP-2. PARP-2, like PARP-1, interacts with B23 through its N-terminal DNA binding domain. This association is constitutive and does not depend on either PARP activity or ribosomal transcription, but is prevented by mutation of the nucleolar localization signal of PARP-2. PARP-1 and PARP-2, together with B23, are delocalized from the nucleolus upon RNA polymerase I inhibition whereas the nucleolar accumulation of all three proteins is only moderately affected upon oxidative or alkylated DNA damage. Finally, we show that murine fibroblasts deficient in PARP-1 or PARP-2 are not affected in the transcription of ribosomal RNAs. Taken together, these results suggest that the biological role of PARP-1 and PARP-2 within the nucleolus relies on functional nucleolar transcription, without any obvious implication of either PARP on this major nucleolar process.
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PMID:PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. 1561 85

The nucleolus is the site of rRNA and ribosome production. This organelle presents an active fibrillogranular ultrastructure in the oocyte during the growth of the gamete but, at the end of the growth phase, the nucleolus is transformed into an inactive remnant that is dissolved when meiosis is resumed at germinal vesicle breakdown. Upon meiosis, structures resembling the nucleolar remnant, now referred to as nucleolus precursor bodies (NPBs), are established in the pronuclei. These entities harbour the development of fibrillogranular nucleoli and re-establishment of nucleolar function in conjunction with the major activation of the embryonic genome. This so-called nucleologenesis occurs at a species-specific time of development and can be classified into two different models: one where nucleolus development occurs inside the NPBs (e.g. cattle) and one where the nucleolus is formed on the surface of the NPBs (e.g. pigs). A panel of nucleolar proteins with functions during rDNA transcription (topoisomerase I, RNA polymerase I and upstream binding factor) and early (fibrillarin) or late rRNA processing (nucleolin and nucleophosmin) are localised to specific compartments of the oocyte nucleolus and those engaged in late processing are, to some degree, re-used for nucleologenesis in the embryo, whereas the others require de novo embryonic transcription in order to be allocated to the developing nucleolus. In the oocyte, inactivation of the nucleolus coincides with the acquisition of full meiotic competence, a parameter that may be of importance in relation to in vitro oocyte maturation. In embryo, nucleologenesis may be affected by technological manipulations: in vitro embryo production apparently has no impact on this process in cattle, whereas in the pig this technology results in impaired nucleologenesis. In cattle, reconstruction of embryos by nuclear transfer results in profound disturbances in nucleologenesis. In conclusion, the nucleolus is an organelle of great importance for the developmental competence of oocytes and embryos and may serve as a morphological marker for the completion of oocyte growth and normality of activation of the embryonic genome.
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PMID:Meiosis and embryo technology: renaissance of the nucleolus. 1574 27

Transcription of the ribosomal RNA (rRNA) genes occurs in the nucleolus and results in ribosome biogenesis. The rRNA gene activation and the associated nucleolus formation may be used as a marker for the activation of the embryonic genome in mammalian embryos and, thus serve to evaluate the developmental potential of embryos originating from varied nuclear transfer protocols. In bovine in vivo developed embryos, functional ribosome-synthesizing nucleoli become structurally distinct toward the end of the 4th post-fertilization cell cycle. In embryonic cell nuclear transfer embryos, fully developed nucleoli are not apparent until the 5th cell cycle, whereas in somatic cell nuclear transfer embryos the functional nucleoli emerge already during the 3rd cell cycle. Intergeneric reconstructed embryos produced by the fusion of bovine differentiated somatic cell to a nonactivated ovine cytoplast fail to develop fully functional nucleoli. In bovine in vivo developed embryos, a range of important nucleolar proteins (e.g., topoisomerase I, upstream binding factor and RNA polymerase I, fibrillarin, nucleophosmin and nucleolin) become localized to the nucleolar anlage over several cell cycles. This relocation is completed toward the end of the 4th cell cycle. A substantial proportion of bovine embryos produced by nuclear transfer of embryonic or somatic cells to bovine ooplasts display aberrations in protein localization in one or more blastomers. This information is indicative of underlying aberrations in genomic reprogramming and may help to explain the abnormalities observed in a proportion of fetuses and offspring derive from nuclear transfer embryos.
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PMID:Nucleolar remodeling in nuclear transfer embryos. 1717 56

The goal of the present study was to investigate whether key nucleolar proteins involved in ribosomal RNA (rRNA) transcription and processing are transcribed de novo or from maternally inherited messenger RNAs (mRNA) in bovine embryos, and to which extent de novo transcription of these proteins mRNA is required for the development of functional nucleoli during the major activation of the embryonic genome. Immunofluorescence for localization of key nucleolar proteins, autoradiography for detection of transcriptional activity, and transmission electron microscopy were applied to in vitro produced bovine embryos cultured from the 2-cell stage with or without (control groups) alpha-amanitin, which blocks the RNA polymerases II and III transcription and, thus the synthesis of mRNA. In the control groups, weak autoradiographic labeling was initially observed in the periphery of few nuclei at the 4-cell and the early 8-cell stage, and the entire nucleoplasm as well as nucleolus precursor bodies (NBBs) were prominently labelled in all late 8-cell stages. The NPBs displayed initial transformation into fibrillo-granular nucleoli. In the alpha-amanitin group, lack of autoradiographic labeling was seen at all developmental stages and disintegrated NPBs stage were found at the late 8-cell. Our immunofluorescence data indicate that RNA polymerase I, UBF, topoisomerase I and fibrillarin are transcribed de novo whereas nucleolin and nucleophosmin are maternally inherited as demonstrated by alpha -amanitin inhibition. However, localization of these two proteins to the nucleolar compartments was negatively affected by the alpha-amanitin treatment. Consequently, functional nucleoli were not established.
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PMID:Nucleolar development and allocation of key nucleolar proteins require de novo transcription in bovine embryos. 1741 May 44

The nucleolus is the site of ribosomal RNA (rRNA) and ribosome production. In the bovine primordial follicle oocyte, this organelle is inactive, but in the secondary follicle an active fibrillo-granular nucleolus develops and proteins involved in rDNA transcription (topoisomerase I, RNA polymerase I and upstream binding factor) and early (fibrillarin) or late rRNA processing (nucleolin and nucleophosmin) localize to it. At the end of the oocyte growth phase, the nucleolus is inactivated again and transforms into a solid remnant. The nucleolar remnant is dissolved when meiosis is resumed. Upon fertilization, structures resembling the nucleolar remnant, now referred to as nucleolus precursor bodies (NPBs), are established in the pronuclei. These entities are engaged in the re-establishment of fibrillo-granular nucleoli at the major activation of the embryonic genome. This nucleolar formation can be classified into two different modes: one where nucleolus development occurs inside NPBs (internal; e.g. cattle) and the other where it occurs on the surface of NPBs (external; e.g. pig). Oocyte derived proteins engaged in late rRNA processing (nucleolin and nucleophosmin) may to some degree be re-used for nucleolar formation in the embryo, while the other nucleolar proteins require de novo embryonic transcription in order to be allocated to the developing nucleoli. Moreover, unprocessed rRNA inherited from the oocyte targets to the developing embryonic nucleoli. In conclusion, the nucleolus is important for the development of oocytes and embryos and may serve as a marker for the completion of oocyte growth and the normality of activation of the embryonic genome.
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PMID:Ribosomal RNA and nucleolar proteins from the oocyte are to some degree used for embryonic nucleolar formation in cattle and pig. 1746 64

Alteration of nuclear morphology is often used by pathologist as diagnostic marker for malignancies like cancer. In particular, the staining of cells by the silver staining methods (AgNOR) has been proved to be an important tool for predicting the clinical outcome of some cancer diseases. Two major argyrophilic proteins responsible for the strong staining of cells in interphase are the nucleophosmin (B23) and the nucleolin (C23) nucleolar proteins. Interestingly these two proteins have been described as chromatin associated proteins with histone chaperone activities and also as proteins able to regulate chromatin transcription. Nucleolin seems to be over-expressed in highly proliferative cells and is involved in many aspect of gene expression: chromatin remodeling, DNA recombination and replication, RNA transcription by RNA polymerase I and II, rRNA processing, mRNA stabilisation, cytokinesis and apoptosis. Interestingly, nucleolin is also found on the cell surface in a wide range of cancer cells, a property which is being used as a marker for the diagnosis of cancer and for the development of anti-cancer drugs to inhibit proliferation of cancer cells. In addition to its implication in cancer, nucleolin has been described not only as a marker or as a protein being involved in many diseases like viral infections, autoimmune diseases, Alzheimer's disease pathology but also in drug resistance. In this review we will focus on the chromatin associated functions of nucleolin and discuss the functions of nucleolin or its use as diagnostic marker and as a target for therapy
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PMID:Functions of the histone chaperone nucleolin in diseases. 1748 27

Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
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PMID:Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. 1837 77

It is extremely rare that a patient with anaplastic large cell lymphoma (ALCL) demonstrates circulating lymphoma cells. A 10-year-old Japanese boy was presented with high-grade fever and cough. The physical examination revealed marked hepatosplenomegaly with ascites and lymphadenopathy in the cervical and periauricular areas. The white cell count was 26.2x10(9)/L with 95% of abnormal lymphoid cells, which were small to medium-sized with a high nucleus/cytoplasm ratio, basophilic cytoplasm, condensed nuclear chromatins, and 1 or 2 distinct nucleoli, hemoglobin 6.4 g/dL, and platelet 0.9x10(9)/L. A flow cytometric analysis of abnormal cells in both the peripheral blood and bone marrow samples was strongly positive for CD30 on their cell membranes. Karyogram and fluorescent in situ hybridization showed abnormal cells to have a characteristic chromosomal translocation, t(2;5)(p23;q35). Reverse transcriptase-polymerase chain reaction of peripheral blood cell-derived mRNA also indicated the fusion gene product of anaplastic lymphoma kinase and nucleophosmin. Subsequently, the patient was diagnosed to have ALCL with a rare clinical feature of a peripheral leukemic presentation, and his disease revealed to be refractory to chemotherapy. On the basis of the 11 childhood cases of ALCL with leukemic presentation so far published and reviewed herein, the prognosis is very poor.
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PMID:Anaplastic large cell lymphoma in leukemic presentation: a case report and a review of the literature. 1877 64

CTCF is a ubiquitous transcription factor that is involved in numerous, seemingly unrelated functions. These functions include, but are not limited to, positive or negative regulation of transcription, enhancer-blocking activities at developmentally regulated gene clusters and at imprinted loci, and X-chromosome inactivation. Here, we review recent data acquired with state-of-the-art technologies that illuminate possible mechanisms behind the diversity of CTCF functions. CTCF interacts with numerous protein partners, including cohesin, nucleophosmin, PARP1, Yy1 and RNA polymerase II. We propose that CTCF interacts with one or two different partners according to the biological context, applying the Roman principle of governance, 'divide and rule' (divide et impera).
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PMID:CTCF and its protein partners: divide and rule? 1938 94


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