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At least 1,099 records · Page 61Linked to original sources
PubMed2005

Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling.

Propionibacterium acnes, an anaerobic pathogen, plays an important role in the pathogenesis of acne and seems to initiate the inflammatory process by producing proinflammatory cytokines. In order to demonstrate the anti-inflammatory effects and action mechanisms of magnolol and honokiol, several methods were employed. Through DPPH and SOD activity assays, we found that although both magnolol and honokiol have antioxidant activities, honokiol has relatively stronger antioxidant activities than magnolol {[for DPPH assay, % of DPPH bleaching of magnolol and honokiol (500 microM magnolol: 19.8%; 500 microM honokiol: 67.3%)]; [for SOD assay, SOD activity (200 microM magnolol: 53.4%; 200 microM honokiol: 64.3%)]}. Moreover, the production of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) induced by P. acnes in THP-1 cells, a human monocytic cell line, was reduced by magnolol and honokiol {[for IL-8 (10 microM magnolol: 42.7% inhibition; 10 microM honokiol: 51.4% inhibition)]; [for TNF-alpha (10 microM magnolol: 20.3% inhibition; 10 microM honokiol: 39.0% inhibition)]}. Cyclooxygenase-2 (Cox-2) activity was also suppressed by them [(15 microM magnolol: 45.8% inhibition), (15 microM honokiol: 66.3% inhibition)]. Using a nuclear factor-kappaB (NF-kappaB) luciferase reporter assay system and Western analysis, we identified that magnolol and honokiol exert their anti-inflammatory effects by inhibiting the NF-kappaB element, which exists in Cox-2, IL-8, and TNF-alpha promoters [(15 microM magnolol: 44.8% inhibition), (15 microM honokiol: 42.3% inhibition)]. Of particular note is that magnolol and honokiol operate downstream of the MEKK-1 molecule. Together with their previously known antibacterial activity against P. acnes and based on these results, we suggest that magnolol and honokiol may be introduced as possible acne-mitigating agents.

Anti-Bacterial Agents↗
PubMed2005

Effect of centrally administered C75, a fatty acid synthase inhibitor, on ghrelin secretion and its downstream effects.

The central administration of the fatty acid synthase (FAS) inhibitor, C75, rapidly suppresses the expression of orexigenic neuropeptides [neuropeptide Y (NPY) and agouti-related protein (AgRP)] and activates expression of anorexigenic neuropeptides [proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)] in the hypothalamus. The combined actions of these changes inhibit food intake and decrease body weight. Intracerebroventricular injection of C75 appears to rapidly inhibit the secretion of ghrelin by hypothalamic explants ex vivo and by the stomach in vivo. Ghrelin administered intracerebroventricularly reverses the anorexic effect of C75, suggesting that C75 acts upstream of ghrelin. Because ghrelin-producing neurons are known to form synapses onto NPY/AgRP neurons, we suggest that the reversal of C75-induced anorexia by ghrelin may be mediated by NPY/AgRP neurons. This hypothesis is supported by the finding that ghrelin reverses the C75-induced inactivation (assessed by c-Fos expression) of neurons in the arcuate nucleus that express NPY (assessed by immunohistochemical costaining). These effects closely correlate with appropriate changes downstream in the expression of the hypothalamic neuropeptides that regulate feeding behavior, i.e., down-regulation of the expression of NPY and AgRP and up-regulation of the expression of proopiomelanocortin/alpha-melanocyte-stimulating hormone, provoked by C75 and reversed by ghrelin. We propose a model in which ghrelin secretion plays an intermediary role between malonyl-CoA, the substrate of fatty acid synthase, and the neural circuitry regulating energy homeostasis.

4-Butyrolactone↗
PubMed2001

TFIIH action in transcription initiation and promoter escape requires distinct regions of downstream promoter DNA.

TFIIH is a multifunctional RNA polymerase II general initiation factor that includes two DNA helicases encoded by the Xeroderma pigmentosum complementation group B (XPB) and D (XPD) genes and a cyclin-dependent protein kinase encoded by the CDK7 gene. Previous studies have shown that the TFIIH XPB DNA helicase plays critical roles not only in transcription initiation, where it catalyzes ATP-dependent formation of the open complex, but also in efficient promoter escape, where it suppresses arrest of very early RNA polymerase II elongation intermediates. In this report, we present evidence that ATP-dependent TFIIH action in transcription initiation and promoter escape requires distinct regions of the DNA template; these regions are well separated from the promoter region unwound by the XPB DNA helicase and extend, respectively, approximately 23-39 and approximately 39-50 bp downstream from the transcriptional start site. Taken together, our findings bring to light a role for promoter DNA in TFIIH action and are consistent with the model that TFIIH translocates along promoter DNA ahead of the RNA polymerase II elongation complex until polymerase has escaped the promoter.

Base Sequence↗
PubMed2002

An Arabidopsis mutation in translation elongation factor 2 causes superinduction of CBF/DREB1 transcription factor genes but blocks the induction of their downstream targets under low temperatures.

Low temperature regulates gene expression in bacteria, yeast, and animals as well as in plants. However, the signal transduction cascades mediating the low temperature responses are not well understood in any organism. To identify components in low temperature signaling genetically, we isolated Arabidopsis thaliana mutants in which cold-responsive genes are no longer induced by low temperatures. One of these mutations, los1-1, specifically blocks low temperature-induced transcription of cold-responsive genes. Surprisingly, cold-induced expression of the early response transcriptional activators, C-repeat/dehydration responsive element binding factors (CBF/DREB1s), is enhanced by the los1-1 mutation. The los1-1 mutation also reduces the capacity of plants to develop freezing tolerance but does not impair the vernalization response. Genetic analysis indicated that los1-1 is a recessive mutation in a single nuclear gene. The LOS1 gene encodes a translation elongation factor 2-like protein. Protein labeling studies show that new protein synthesis is blocked in los1-1 mutant plants specifically in the cold. These results reveal a critical role of new protein synthesis in the proper transduction of low temperature signals. Our results also suggest that cold-induced transcription of CBF/DREB1s is feedback inhibited by their gene products or by products of their downstream target genes.

Amino Acids↗
PubMed2002

Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of TSC2 derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling.

The Hairy-related transcription-factor (HRT) genes encode three related basic helix-loop-helix transcription factors that show sequence similarity to the Hairy and Enhancer of split family of transcriptional repressors. HRT proteins are expressed in specific regions of the developing heart, vasculature, pharyngeal arches and somites, and the periodicity of their expression in somitic precursors mirrors that of Notch signaling-related molecules. In the present study, we show that the intracellular domain of the Notch1 receptor (Notch1 IC), which is constitutively active, up-regulates HRT2 expression in 10T(1/2) fibroblasts. Luciferase reporter assays using the regulatory regions of the mouse HRT genes revealed that transcription of all three genes is stimulated by Notch1 IC. The promoters of the HRT genes share homology in a binding site for Suppressor of Hairless [Su(H)], a transcriptional mediator of Notch signaling. A dominant-negative Su(H) mutant abolished Notch-activated HRT2 expression, and mutation of the conserved Su(H) consensus site in the HRT2 promoter attenuated transcriptional activation by Notch. Ectopic expression of HRT proteins also blocked activation of HRT2 expression by Notch1 IC through a mechanism requiring the basic region, but not the conserved carboxyl-terminal YQPW-TEVGAF motif of HRT2. These findings identify HRT genes as downstream targets for Notch signaling and reveal a negative autoregulatory loop whereby HRT proteins repress their own expression through interference with Notch signaling.

Animals↗
PubMed1981

Cloning and analysis of strong promoters is made possible by the downstream placement of a RNA termination signal.

Downstream placement of a strong transcriptional termination signal has made possible the cloning of bacteriophage T5 promoters known to exhibit high signal strength. The cloning system constructed contains two easily assayable indicator functions whose expression is controlled by the integration of promoters and terminators, respectively. By assessing transcription within the indicator regions, the efficiency of promoters as well as termination signals can be determined in vitro and in vivo.

Base Sequence↗
PubMed1985

A sequence downstream of A-A-U-A-A-A is required for formation of simian virus 40 late mRNA 3' termini in frog oocytes.

The 3' terminus of simian virus 40 late mRNA is formed by nucleolytic cleavage of an mRNA precursor. In this report we show that efficient cleavage requires a sequence in the 3' flanking region, "downstream" of the highly conserved A-A-U-A-A-A sequence. This sequence is not required for polyadenylylation itself or for accurately positioning the 3' terminus that is formed.

Animals↗
PubMed1985

Chromatin structure around the c-myc gene in Burkitt lymphomas with upstream and downstream translocation points.

Burkitt lymphoma cells seem to have abnormal c-myc gene activity resulting from chromosomal translocation. We have examined the consequences of translocation on putative control sequences near to the c-myc gene by DNase I hypersensitivity mapping of chromatin. There is no detectable difference in the pattern of hypersensitivity (compared with the actively transcribed c-myc gene of lymphoblastoid cells) in Burkitt lymphoma cells where the translocation point occurs at a considerable distance upstream or downstream of c-myc. When the translocation occurs near the 5' end of the c-myc gene, resulting in loss of hypersensitive sites, those that remain show the same sensitivity as in lymphoblastoid cell lines. We conclude that translocation has little general effect on the usual pattern of hypersensitive sites near to the c-myc gene but new sites can be observed in some cases in the immunoglobulin region near to the breakpoint. These may be sites normally involved in immunoglobulin gene transcription and may exert a subtle effect on the translocated c-myc gene.

Base Sequence↗
PubMed1987

A poly(A) addition site and a downstream termination region are required for efficient cessation of transcription by RNA polymerase II in the mouse beta maj-globin gene.

Sequence elements within the mouse beta maj-globin transcription unit required for efficient termination of transcription by RNA polymerase II have been delineated. To facilitate nascent-chain analysis of termination, the DNA segment in which transcription ceases was introduced into the adenovirus chromosome within its E1A transcription unit. Two beta-globin DNA elements were required to effect efficient termination: an upstream sequence that includes two poly(A) addition signals and a downstream region previously shown to be where RNA synthesis stops. The role of poly(A) addition in termination was established by introduction of several single base pair substitutions into the AATAAA polyadenylylation motifs. These mutations inhibited both polyadenylylation and termination within the beta-globin DNA segment. Therefore, poly(A) addition appears to be a prerequisite for efficient termination.

Animals↗
PubMed1987

The breakpoint of an inversion of chromosome 14 in a T-cell leukemia: sequences downstream of the immunoglobulin heavy chain locus are implicated in tumorigenesis.

T-cell tumors are characterized by inversions or translocations of chromosome 14. The breakpoints of these karyotypic abnormalities occur in chromosome bands 14q11 and 14q32--the same bands in which the T-cell receptor (TCR) alpha-chain and immunoglobulin heavy chain genes have been mapped, respectively. Patients with ataxia-telangiectasia are particularly prone to development of T-cell chronic lymphocytic leukemia with such chromosomal abnormalities. We now describe DNA rearrangements of the TCR alpha-chain gene in an ataxia-telangiectasia-associated leukemia containing both a normal and an inverted chromosome 14. The normal chromosome 14 has undergone a productive join of TCR alpha-chain variable (V alpha) and joining (J alpha) gene segments. The other allele of the TCR alpha-chain gene features a DNA rearrangement, about 50 kilobases from the TCR alpha-chain constant (C alpha) gene, that represents the breakpoint of the chromosome 14 inversion; this breakpoint is comprised of a TCR J alpha segment (from 14q11) fused to sequences derived from 14q32 but on the centromeric side of C mu. These results imply that 14q32 sequences located at an undetermined distance downstream of the immunoglobulin C mu locus can contribute to the development of T-cell tumors.

Ataxia Telangiectasia↗
PubMed1988

NusA protein is necessary and sufficient in vitro for phage lambda N gene product to suppress a rho-independent terminator placed downstream of nutL.

Transcription antitermination by phage lambda N protein is reproduced in vitro solely with purified components. We have placed a strong rho-independent terminator, lambda tR', in the PL operon about 200 base pairs downstream from the N-recognition site, nutL, and have monitored terminated and run-off transcripts produced by single-round transcription of linear plasmids. In the presence of NusA, one of several host factors implicated in antitermination, N is found to virtually abolish termination at tR'. N is unable to suppress termination if the terminator is preceded by a defective nut site. Thus, during transcription through the nut site, N and NusA can modify RNA polymerase to a termination-resistant form in the absence of any other accessory factor.

Bacterial Proteins↗
PubMed1990

An RNA polymerase II promoter containing sequences upstream and downstream from the RNA startpoint that direct initiation of transcription from the same site.

The gfa gene encodes glial fibrillary acidic protein (GFAP), an intermediate-filament protein expressed primarily in glial cells. We have used in vitro transcription studies to show that the basal level of transcription of the human gene encoding GFAP is controlled by two distinct initiators--i.e., promoter elements that direct transcription from a specific start site. One initiator is located about 25 base pairs upstream from the transcription start site, contains a TATA box, and apparently acts together with a sequence found around the transcription start site. The other initiator is located between +11 and +50 bp downstream from the transcription start site. Most of this second region overlaps with the protein-encoding sequence, which starts at bp +17. The sensitivity of transcription to alpha-amanitin indicates that both initiators are used by RNA polymerase II.

Amino Acid Sequence↗
PubMed1991

Drosophila retrotransposon promoter includes an essential sequence at the initiation site and requires a downstream sequence for full activity.

We describe a 98-base-pair region (-38 to +60) in the long terminal repeat of the Drosophila gypsy retrotransposon that is sufficient for accurate normal-level transcription. We find that, unlike most RNA polymerase II (pol II) promoters, the gypsy promoter includes downstream sequences that are required for full activity. Also unlike most pol II promoters, the gypsy promoter, which lacks a TATA motif, was found to have an essential sequence at the transcription initiation site, mutation of which abolishes transcription. These three uncommon features of the gypsy promoter may be characteristic of a subset of pol II promoters, exemplified by certain retrotransposons and developmental genes of Drosophila and by Tdt, the mouse terminal deoxynucleotidyl-transferase (TdT) gene.

Animals↗
PubMed1992

MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts.

The pathogenetic mechanism of the mitochondrial tRNA(LeuUUR) gene mutation responsible for the MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) syndrome was investigated in transformants obtained by transfer of mitochondria from three genetically unrelated MELAS patients into human mitochondrial DNA (mtDNA)-less (rho 0) cells. Marked defects in mitochondrial protein synthesis and respiratory activity were observed in transformants containing virtually pure mutant mtDNA, as compared to the parent of the rho 0 cells (the 143B cell line) or to transformants containing exclusively wild-type mtDNA, derived from one of the patients or a maternally related asymptomatic individual. A striking protective effect against the mutation was exerted in the transformants by levels of residual wild-type mtDNA above 6%. The MELAS mutation occurs within the mtDNA binding site for a protein factor (mTERF) that promotes termination of transcription at the 16S rRNA/tRNA(LeuUUR) gene boundary. A marked decrease in affinity of purified mTERF for the mutant target sequence was observed in in vitro assays. By contrast, RNA transfer hybridization experiments failed to show any significant change in the steady-state amounts of the two rRNA species, encoded upstream of the termination site, and of the mRNAs encoded downstream, in the transformants carrying the MELAS mutation.

Acidosis, Lactic↗
PubMed1993

Transcription factor TFIID recognizes DNA sequences downstream of the TATA element in the Hsp70 heat shock gene.

The interaction between the Hsp70 heat shock gene promoter and a Drosophila protein complex which contains the TATA-binding protein depends on sequence-specific interactions located in the region downstream of the transcription start site. Immunopurification of the complex through the use of antibodies against the TATA-binding protein reveals that the complex is transcription factor TFIID. Binding assays with the immunopurified TFIID confirm that sequence-specific contacts are made in the region between nucleotides +18 and +33 relative to the transcription start site. These sequence-specific interactions could play key roles in recognition of TATA-containing and TATA-less promoters.

Animals↗
PubMed1993

Transcriptional regulatory elements downstream of the JunB gene.

JunB is an immediate early transcription factor that is induced by a variety of extracellular signaling agents, including growth factors, phorbol esters, and agents that elevate cyclic AMP. The mechanism of activation of the gene encoding JunB by these agents is not well understood. By using the JunB gene together with flanking DNA in transfection experiments, we show that a serum response element (SRE) and/or a cAMP response element (CRE) downstream of the gene mediate the response of the gene in mouse NIH 3T3 cells to serum, platelet-derived growth factor, basic fibroblast growth factor, phorbol ester, and forskolin. In addition, a segment of DNA just upstream of the TATA box is required for optimal activation of the gene.

3T3 Cells↗
PubMed1995

Dual transcriptional control by Ear3/COUP: negative regulation through the DR1 direct repeat and positive regulation through a sequence downstream of the transcriptional start site of the mouse mammary tumor virus promoter.

Ear3/COUP is an orphan member of the steroid/thyroid hormone receptor superfamily of transcription factors and binds most tightly to a direct repeat of AGGTCA with 1 nucleotide in between (DR1). Ear3/COUP also binds with a similar affinity to the palindromic thyroid hormone response element (TRE). This binding preference of Ear3/COUP is same as that of the retinoid X receptor (RXR), which is another member of the superfamily. In the present study, we identified a sequence responsible for Ear3/COUP-mediated transactivation in the region downstream of the transcription start site of the mouse mammary tumor virus promoter. This cis-acting sequence was unresponsive to RXR. When the DR1 or TRE sequence was added upstream of the promoter, transactivation by Ear3/COUP was completely abolished, whereas RXR enhanced transcription from the promoter. The mode of action of Ear3/COUP could be utilized to control complex gene expressions in morphogenesis, homeostasis, and development.

Animals↗