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At least 811 records · Page 45Linked to original sources
PubMed1997

Distribution of the messenger RNA for the extracellularly regulated kinases 1, 2 and 3 in rat brain: effects of excitotoxic hippocampal lesions.

Neurofibrillary tangles in Alzheimer's disease are composed of hyperphosphorylated forms of the microtubule-associated protein tau. Based on biochemical criteria, several enzymes have emerged as potential tau protein kinases, including the extracellularly regulated kinases 1, 2 and 3. In situ hybridization was used to map the messenger RNA distribution of extracellularly regulated kinase 1, 2 and 3 in the adult rat brain and their response to excitotoxic hippocampal lesions was examined. Extracellularly regulated kinase 1 messenger RNA was uniformly expressed by glia, but was also present in the dentate gyrus and some other neuronal populations. Extracellularly regulated kinase 2 was exclusively neuronal and concentrated within the cortical laminae and the CA subfields of the hippocampal formation. Extracellularly regulated kinase 3 messenger RNA expression was similar to extracellularly regulated kinase 2 and was also present in neurons but the level of expression was lower. Extracellularly regulated kinases 2 and 3 messenger RNA expression was lost following excitotoxic injury, further supporting a neuronal localization. Extracellularly regulated kinase 1 messenger RNA expression appeared unaltered, suggesting a non-neuronal localization and lack of responsiveness to lesion at the level of transcription. By contrast, messenger RNA of sgk, a recently described serine/threonine kinase, was up-regulated by glial cells following excitotoxic injury. Based on their messenger RNA distribution, cellular localization and response to lesion, it is clear that each kinase may function differently in various signaling pathways. Extracellularly regulated kinase 2, however, is the only kinase with the proper messenger RNA distribution to contribute to neurofibrillary tangle formation in Alzheimer's disease.

Animals↗
PubMed1993

Roles of nonstructural polyproteins and cleavage products in regulating Sindbis virus RNA replication and transcription.

Using vaccinia virus to express Sindbis virus (SIN) nonstructural proteins (nsPs) and template RNAs, we showed previously that synthesis of all three viral RNAs occurred only during expression of either the entire nonstructural coding region or the polyprotein precursors P123 and P34. In this report, the vaccinia virus system was used to express cleavage-defective polyproteins and nsP4 proteins containing various N-terminal extensions to directly examine the roles of the P123 and P34 polyproteins in RNA replication. Replication and subgenomic mRNA transcription occurred during coexpression of P34 and P123 polyproteins in which cleavage was blocked at either or both of the 1/2 and 2/3 sites. For all cleavage-defective P123 polyproteins, however, the ratio of subgenomic to genomic RNA was decreased, suggesting that both the 1/2 and 2/3 cleavages are required for efficient subgenomic RNA transcription. These studies indicate that the uncleaved P123 polyprotein can function as a component of the viral replicase capable of synthesizing both plus- and minus-strand RNAs. In contrast, cleavage-defective P34 was unable to function in RNA replication, even in complementation experiments in which minus-strand RNAs were provided by nsP4. A P34 polyprotein whose cleavage site was not altered could only function in RNA replication in the presence of an active nsP2 protease. Although nsP4, the putative RNA polymerase, was capable of synthesizing only minus-strand RNAs during coexpression with P123, the addition of only 22 upstream residues to nsP4 allowed both replication and transcription of subgenomic RNA to occur. These data show that the conserved domains of both nsP3 and the nsP4 polymerase do not need to be present in a P34 polyprotein to form a functional plus-strand replicase-transcriptase and suggest that the presence of an active nsP2 protease and a cleavable 3/4 site correlates with synthesis of all virus-specific RNA species.

Animals↗
PubMed1999

Direct regulation of mitochondrial RNA synthesis by thyroid hormone.

We have analyzed the influence of in vivo treatment and in vitro addition of thyroid hormone on in organello mitochondrial DNA (mtDNA) transcription and, in parallel, on the in organello footprinting patterns at the mtDNA regions involved in the regulation of transcription. We found that thyroid hormone modulates mitochondrial RNA levels and the mRNA/rRNA ratio by influencing the transcriptional rate. In addition, we found conspicuous differences between the mtDNA dimethyl sulfate footprinting patterns of mitochondria derived from euthyroid and hypothyroid rats at the transcription initiation sites but not at the mitochondrial transcription termination factor (mTERF) binding region. Furthermore, direct addition of thyroid hormone to the incubation medium of mitochondria isolated from hypothyroid rats restored the mRNA/rRNA ratio found in euthyroid rats as well as the mtDNA footprinting patterns at the transcription initiation area. Therefore, we conclude that the regulatory effect of thyroid hormone on mitochondrial transcription is partially exerted by a direct influence of the hormone on the mitochondrial transcription machinery. Particularly, the influence on the mRNA/rRNA ratio is achieved by selective modulation of the alternative H-strand transcription initiation sites and does not require the previous activation of nuclear genes. These results provide the first functional demonstration that regulatory signals, such as thyroid hormone, that modify the expression of nuclear genes can also act as primary signals for the transcriptional apparatus of mitochondria.

Animals↗
PubMed1993

Polyoma virus early-late switch: regulation of late RNA accumulation by DNA replication.

Early in infection of permissive mouse cells, messages from the early region of the polyoma virus genome accumulate preferentially over those from the late region. After initiation of DNA replication, the balance between early and late gene expression is reversed in favor of the late products. In previous work from our laboratory, we showed that viral early proteins do not activate the polyoma late promoter in the absence of DNA replication. Here we show that activation of the late genes in replication-incompetent viral genomes can occur if actively replicating genomes are present in the same cell. A low level of DNA replication, however, is insufficient to induce the early-late switch. Furthermore, replication-competent genomes that fail to accumulate late RNA molecules are defective in the transactivation of replication-incompetent genomes. We suggest that titration of an unknown diffusible factor(s) after DNA replication relieves the block to late RNA accumulation seen in the early phase, with most of this titration being attributable to late-strand RNA molecules themselves.

3T3 Cells↗
PubMed2001

Perforant path lesion induces up-regulation of stathmin messenger RNA, but not SCG10 messenger RNA, in the adult rat hippocampus.

In this study, we performed in situ hybridization analysis of the expression pattern of two growth-associated proteins, stathmin and SCG10, in the hippocampus after unilateral lesion of the perforant pathway, the main excitatory input from the entorhinal cortex to the hippocampus. Stathmin is one of the major neural-enriched cytosolic phosphoproteins and a potential target of cyclic-AMP-dependent kinases [Jin L. W. et al. (1996) Neurobiol. Aging 17, 331-341; Leighton I. A. et al. (1993) Molec. Cell Biochem. 127/128, 151-156]. Three days after the lesion, stathmin messenger RNA was up-regulated ipsilaterally in the hilus, in the granule cell layer of the dentate gyrus and in the pyramidal cell layer of the CA1 region. Simultaneously, the hilar region of the contralateral dentate gyrus showed an increased stathmin messenger RNA expression. This altered expression pattern was observed until 15 days after lesion. Stathmin messenger RNA expression returned to a normal level until 21 days after lesion in all regions analysed. SCG10, a membrane-bound neuronal growth-associated protein belonging to the SCG10/stathmin gene family, did not show any alteration of messenger RNA expression after perforant path lesion. The temporal changes of stathmin messenger RNA expression in the ipsilateral hippocampus correspond well to the process of reactive synaptogenesis. The enhanced messenger RNA expression in the hilar region of the contralateral dentate gyrus might suggest a role in neurite elongation, since this region is the origin of commissural fibres involved in the sprouting response in the deafferented hippocampus. The present study provides evidence that the induction of specific growth-associated proteins is differentially regulated in the hippocampus.

Animals↗
PubMed1981

Small nuclear RNA molecules that regulate nuclease accessibility in specific chromatin regions of meiotic cells.

One of the factors regulating the accessibility of specific DNA sequences to endonuclease nicking during meiosis is a group of small nuclear RNA molecules, 125 nucleotides in length and transcribed by RNA polymerase III. These molecules (referred to as PsnRNA) are synthesized during meiotic prophase, when chromosomes are undergoing homologous pairing or are already paired. Accessibility to the meiotically active DNA sequences (P DNA) depends on an as-yet-undefined alteration in chromatin structure. PsnRNA is a critical factor in the alteration; it cannot be replaced by other forms of RNA. The specificity of the chromatin sites altered by PsnRNA appears to be a function of sequence complementarity between it and P DNA. Under in vivo conditions the effective action of PsnRNA depends on homologous chromosome pairing. Chromatin sites housing P-DNA sequences in nuclei isolated from cells lacking homologous pairing are not affected by meiotic endonuclease or DNAse II. Accessibility to these sites can be effected by incubation of the nuclei with PsnRNA, but only if the nuclei are from zygotene-pachytene cells. Analyses of pachytene nuclei preincubated with PsnRNA indicate that PsnRNA renders chromatin accessible to at least two endonucleases, meiotic endonuclease and DNAase II, and that it also limits such accessibility to regions housing the complementary P-DNA sequences.

Base Sequence↗
PubMed2025

The small nucleolar RNA NON-CODING RNA 1 negatively regulates drought tolerance in Arabidopsis thaliana.

Small nucleolar RNAs (snoRNAs) function in ribosome biogenesis, and many ribosome biogenesis-related genes were downregulated by osmotic stress, implying a negative role of snoRNAs in drought tolerance. A snoRNA, namely, the NON-CODING RNA 1 (NCR1) was studied for its roles in drought tolerance in Arabidopsis. In comparison with wild-type (WT) plants, the loss-of-function ncr1 mutant plants showed enhanced drought tolerance, which was restored in the NCR1-complemented plants, whereas the NCR1-overexpressing plants revealed a drought-sensitive phenotype. Physiological analyses revealed that the ncr1 plants had a higher leaf surface temperature, lower water loss rates, and improved cell membrane integrity compared with WT. Comparative leaf transcriptomics and proteomics suggested that wax biosynthesis, anthocyanin metabolism, and leaf senescence processes are regulated by NCR1 under both normal and water-deficit conditions. Under drought, an increase in wax and anthocyanin accumulations and a delay in leaf senescence in ncr1 plants, when compared with WT, supported the transcriptome and proteomics data. Additionally, the ncr1 plants exhibited higher abscisic acid (ABA) sensitivity and longer root hairs than WT. Collectively, our results suggest that NCR1 negatively regulates drought tolerance through modification of wax biosynthesis, anthocyanin accumulation, leaf senescence, cell membrane integrity, ABA responses, and root hair development.

Arabidopsis↗
PubMed1993

Developmental expression of chicken antithrombin III is regulated by increased RNA abundance and intracellular processing.

We isolated and sequenced a 432 bp cDNA to cAT-III, that encoded 115 nucleotides of 5' untranslated sequence, a 17 amino acid long signal peptide and residues 1-88 of the mature protein, and used it to prepare a probe for measuring and correlating the developmental changes of steady-state cAT-III mRNA levels with known changes in antigen levels. Densitometric analysis of nuclease protection (n = 2), Northern blot (n = 4), and slot blots (n = 3) of total RNA from chick livers of 16-day-old embryos to 6-day-old chicks showed a 2.6 +/- 0.5-fold increase in steady-state cAT-III mRNA levels. Assay of functional mRNA levels by in vitro translation of poly(A)+ RNA and specific immunoprecipitation of 35S-Met-labelled cAT-III was comparable to RNA analysis (16-day-old embryos vs. 10-day-old hatchlings). We evaluated whether there were developmental differences in post-translational secretion which may also contribute to the regulation of the circulating level of this protein. Pulse-chase studies of freshly-isolated hepatocytes from 16-day-old embryos and 10-day-old hatchlings maintained in suspension demonstrated a approx. 5.0-5.5-fold increase in cAT-III levels at steady-state secretion. The above findings indicate that changes in circulating cAT-III levels during late embryonic development are primarily due to increased abundance of cAT-III mRNA. In addition, we postulate that post-translational intracellular processing may account for further differences in circulating protein levels.

Animals↗
PubMed2004

Regulation of 6S RNA biogenesis by switching utilization of both sigma factors and endoribonucleases.

In Escherichia coli, 6S RNA functions as a modulator of RNA polymerase sigma70-holoenzyme activity, but its biosynthetic pathway remains uncharacterized. In this study, to further understand the regulatory circuit of 6S RNA biosynthesis for the modulation of Esigma70 activity, we have characterized the biogenesis of 6S RNA. We reveal that there are two different precursors, a long and a short molecule, which are transcribed from the distal P2 and proximal P1 promoter, respectively. Transcription from the P2 promoter is both sigma70- and sigmaS-dependent, whereas, in contrast, P1 transcription is sigma70- but not sigmaS-dependent. Both precursors are processed to generate the 5' end of 6S RNA, and while the long precursor is processed exclusively by RNase E, the short precursor is processed by both RNase G and RNase E. Our data indicate that the switching of the utilization of both sigma factors and endoribonucleases in the biogenesis of 6S RNA would play an essential role in modulating its levels in E.coli.

Base Sequence↗
PubMed1994

The nucleus-limited Hsr-omega-n transcript is a polyadenylated RNA with a regulated intranuclear turnover.

The Drosophila Hsr-omega puff, one of the largest heat shock puffs, reveals a very unusual gene, identified by heat shock but constitutively active in nearly all cell types. Surprisingly, Hsr-omega yields two transcription end-products with very different roles. The larger, omega-n, is a nuclear RNA with characteristics suggesting a new class of nuclear RNAs. Although it neither leaves the nucleus nor undergoes processing, omega-n RNA is polyadenylated, showing that polyadenylation is not limited to cytoplasmic RNA, but possibly has a function in the nucleus. The amount of omega-n within the nucleus is specifically regulated by both transcription and turnover. Heat shock and several other agents cause rapid increases in omega-n. A rapid return to constitutive levels follows withdrawal of the agents. Degradation of omega-n is inhibited by actinomycin D, suggesting a novel intranuclear mechanism for RNA turnover. Within the nucleus, some omega-n RNA is concentrated at the transcription site; however, most is evenly distributed over the nucleus, showing no evidence of a concentration gradient which might be produced by simple diffusion from the site of transcription. Previous studies suggested that omega-n has a novel regulatory role in the nucleus. The actinomycin D-sensitive degradation system makes possible rapid changes in the amount of omega-n, allowing the putative regulatory activities to reflect cellular conditions at a given time. Omega-n differs from the best studied nuclear RNAs, snRNAs, in many ways. Omega-n demonstrates the existence of intranuclear mechanisms for RNA turnover and localization that may be used by a new class of nuclear RNAs.

Animals↗
PubMed2004

Regulation of ribosomal RNA gene expression in porcine oocytes.

In vitro production (IVP) of porcine embryos including in vitro maturation (IVM) of oocytes followed by in vitro fertilization (IVF) and in vitro culture (IVC) of the resultant embryos may result in live offspring, but it is still associated with great inefficiencies probably due to incomplete cytoplasmic maturation of the oocytes in vitro. Therefore, fundamental knowledge on the regulation of transcription during the oocyte growth phase when the messengers and protein synthetic machinery necessary for oocyte developmental competence are formed, is of great importance. In mammals, synthesis of RNA, up to 60-70% of which is ribosomal (rRNA), increases during oocyte growth and reaches a peak at the beginning of follicular antrum formation. In oocytes at the end of the growth phase, acquisition of full meiotic competence coincides with a markedly decreased rRNA transcriptional activity in the gametes. Our recent studies on the porcine oocyte growth phase have revealed a deeper molecular and biological insight into the complex regulation of rRNA transcription at different stages of follicular development. The data indicate that the so-called pocket protein, p130, is involved in the down-regulation of rRNA transcription at the end of the oocyte growth phase through an inhibition of the action of upstream binding factor (UBF). The latter protein is necessary for the function of RNA polymerase I (RNA Pol I), which is the actual enzyme driving rRNA gene transcription. Moreover, rRNA transcription also appears to be down-regulated by a decrease in the expression of mRNA encoding PAF53, an RNA Pol I-associated factor also required for the polymerase to exert its action. At the ultrastructural level, these molecular changes are paralleled by marginalization of the fibrillar centres of the oocyte nucleolus followed by compaction of the nucleolus into an inactive sphere of fibrils.

Animals↗
PubMed1994

Cyclic AMP regulation of messenger RNA level of the stimulatory GTP-binding protein Gs alpha. Isoproterenol, forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate increase the level of Gs alpha mRNA in cultured astroglial cells.

The existence of a cAMP-dependent regulation of the expression of the alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gs) in a well characterized astroglial cells culture was established. The culture of astroglial cells for 3-6 h with isoproterenol (10 microM) or forskolin (10 microM) (a cAMP-inducing agent) increased (200-400%) the response of adenylylcyclase to agents which bypass the receptor; GTP, GTP[S] or forskolin. For prolonged exposure times (15 h or more) to isoproterenol or forskolin, the adenylycyclase activity decreased to the value observed in control cells. The same biphasic response of adenylylcyclase to isoproterenol (10 microM) plus GTP (10 microM) occurred in membrane fractions from cells cultured with forskolin, whereas a diminished response to isoproterenol was observed in isoproterenol-treated cells, indicating that the beta-adrenergic receptor was desensitized. To understand the molecular mechanism of these phenomena, we measured the levels of the alpha subunits of the guanine-nucleotide binding protein (Gs and Gi) by Western-blot analysis. The culture of astroglial cells with isoproterenol or forskolin (3-24 h) resulted in a transient increase of both the Gs alpha and the Gi alpha protein levels, while the level of G beta subunits was unaffected. We also identified Gs alpha protein (about 40% of the total cellular protein) in the supernatant fraction of astroglial cells but its level was not modified by the stimulation of cells by forskolin. The level of Gs alpha mRNA measured by Northern-blot analysis was transiently increased (200%) after stimulation of astroglial cells with isoproterenol or forskolin for an incubation period of 6-9 h, then returned to that of control cells for longer period of time. In addition, the Gs alpha mRNA level was threefold increased when cells were cultured for 2-6 h with 8-bromoadenosine 3':5'-cyclic monophosphate (10 microM), a permeant analogue of cAMP. These results indicate that cAMP induces a time-dependent increase of Gs alpha mRNA. The half-life of Gs alpha protein and Gs alpha mRNA were determined. Pulse-chase studies revealed that the decay of Gs alpha protein was clearly biphasic with an early phase (5-6 h) and a slower second phase (20-25 h) but the treatment of cells with forskolin did not accelerate or slow down the turnover of Gs alpha protein.(ABSTRACT TRUNCATED AT 400 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1988

Regulation of host RNA levels during baculovirus infection.

During infection of the permissive host insect cell line Spodoptera frugiperda IPLB-SF-21 by the baculovirus Autographa californica nuclear polyhedrosis virus (AcMNPV), the levels of host actin, histone, and heat shock 70 (hsp70) RNAs are reduced substantially. Reduction of the host RNA levels occurs primarily during a narrow window of the replication process, from approximately 12 to 18 hr postinfection (p.i.), corresponding to the phase in which the extracellular form of the virus buds into the media. A late viral protein appears to be required for this reduction since cycloheximide, an inhibitor of cytosolic protein synthesis, and aphidicolin, an inhibitor of host and viral DNA polymerases, inhibit the reduction of actin and histone RNA levels. A cDNA corresponding to the carboxyl half of the S. frugiperda mitochondrial cytochrome c oxidase subunit III (COIII) gene was isolated, sequenced, and characterized. Two differentially regulated mitochondrial transcripts of this gene are observed. The level of the larger of these transcripts, which is dependent on active cytosolic protein synthesis, is reduced during virus infection in a fashion similar to that of the nuclear host genes. The smaller COIII transcript is stable until at least 24 hr p.i. but the level of this RNA eventually declines by 48 hr p.i.

Actins↗
PubMed2006

Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II.

Over the past years, a large number of histone posttranslational modifications have been described, some of which function to attain a repressed chromatin structure, while others facilitate activation by allowing access of regulators to DNA. Histone H2B monoubiquitination is a mark associated with transcriptional activity. Using a highly reconstituted chromatin-transcription system incorporating the inducible RARbeta2 promoter, we find that the establishment of H2B monoubiquitination by RNF20/40 and UbcH6 is dependent on the transcription elongation regulator complex PAF, the histone chaperone FACT, and transcription. H2B monoubiquitination facilitates FACT function, thereby stimulating transcript elongation and the generation of longer transcripts. These in vitro analyses and corroborating in vivo experiments demonstrate that elongation by RNA polymerase II through the nucleosomal barrier is minimally dependent upon (1) FACT and (2) the recruitment of PAF and the H2B monoubiquitination machinery.

Animals↗
PubMed2003

Characterization of RNA elements that regulate gag-pol ribosomal frameshifting in equine infectious anemia virus.

Synthesis of Gag-Pol polyproteins of retroviruses requires ribosomes to shift translational reading frame once or twice in a -1 direction to read through the stop codon in the gag reading frame. It is generally believed that a slippery sequence and a downstream RNA structure are required for the programmed -1 ribosomal frameshifting. However, the mechanism regulating the Gag-Pol frameshifting remains poorly understood. In this report, we have defined specific mRNA elements required for sufficient ribosomal frameshifting in equine anemia infectious virus (EIAV) by using full-length provirus replication and Gag/Gag-Pol expression systems. The results of these studies revealed that frameshifting efficiency and viral replication were dependent on a characteristic slippery sequence, a five-base-paired GC stretch, and a pseudoknot structure. Heterologous slippery sequences from human immunodeficiency virus type 1 and visna virus were able to substitute for the EIAV slippery sequence in supporting EIAV replication. Disruption of the GC-paired stretch abolished the frameshifting required for viral replication, and disruption of the pseudoknot reduced the frameshifting efficiency by 60%. Our data indicated that maintenance of the essential RNA signals (slippery sequences and structural elements) in this region of the genomic mRNA was critical for sufficient ribosomal frameshifting and EIAV replication, while concomitant alterations in the amino acids translated from the same region of the mRNA could be tolerated during replication. The data further indicated that proviral mutations that reduced frameshifting efficiency by as much as 50% continued to sustain viral replication and that greater reductions in frameshifting efficiency lead to replication defects. These studies define for the first time the RNA sequence and structural determinants of Gag-Pol frameshifting necessary for EIAV replication, reveal novel aspects relative to frameshifting elements described for other retroviruses, and provide new genetic determinants that can be evaluated as potential antiviral targets.

Animals↗
PubMed2002

Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.

Micro-RNAs (miR genes) are a large family of highly conserved noncoding genes thought to be involved in temporal and tissue-specific gene regulation. MiRs are transcribed as short hairpin precursors ( approximately 70 nt) and are processed into active 21- to 22-nt RNAs by Dicer, a ribonuclease that recognizes target mRNAs via base-pairing interactions. Here we show that miR15 and miR16 are located at chromosome 13q14, a region deleted in more than half of B cell chronic lymphocytic leukemias (B-CLL). Detailed deletion and expression analysis shows that miR15 and miR16 are located within a 30-kb region of loss in CLL, and that both genes are deleted or down-regulated in the majority ( approximately 68%) of CLL cases.

Adult↗