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Results for “regulatory module”

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PubMed2006

Downstream regulatory element antagonistic modulator regulates islet prodynorphin expression.

Calcium-binding proteins regulate transcription and secretion of pancreatic islet hormones. Here, we demonstrate neuroendocrine expression of the calcium-binding downstream regulatory element antagonistic modulator (DREAM) and its role in glucose-dependent regulation of prodynorphin (PDN) expression. DREAM is distributed throughout beta- and alpha-cells in both the nucleus and cytoplasm. As DREAM regulates neuronal dynorphin expression, we determined whether this pathway is affected in DREAM(-/-) islets. Under low glucose conditions, with intracellular calcium concentrations of <100 nM, DREAM(-/-) islets had an 80% increase in PDN message compared with controls. Accordingly, DREAM interacts with the PDN promoter downstream regulatory element (DRE) under low calcium (<100 nM) conditions, inhibiting PDN transcription in beta-cells. Furthermore, beta-cells treated with high glucose (20 mM) show increased cytoplasmic calcium (approximately 200 nM), which eliminates DREAM's interaction with the DRE, causing increased PDN promoter activity. As PDN is cleaved into dynorphin peptides, which stimulate kappa-opioid receptors expressed predominantly in alpha-cells of the islet, we determined the role of dynorphin A-(1-17) in glucagon secretion from the alpha-cell. Stimulation with dynorphin A-(1-17) caused alpha-cell calcium fluctuations and a significant increase in glucagon release. DREAM(-/-) islets also show elevated glucagon secretion in low glucose compared with controls. These results demonstrate that PDN transcription is regulated by DREAM in a calcium-dependent manner and suggest a role for dynorphin regulation of alpha-cell glucagon secretion. The data provide a molecular basis for opiate stimulation of glucagon secretion first observed over 25 years ago.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2005

Regulatory T cells modulate Th2 responses induced by Brugia pahangi third-stage larvae.

Infection of BALB/c mice with Brugia pahangi third-stage larvae (L3) results in the production of interleukin-4 (IL-4), IL-5, and IL-10 with a resultant down-regulation in Th1 responses. Previously, this was thought to reflect a skewing of immune responses towards a Th2 phenotype by the infective stage of the parasite. In this study, we show that exposure to the L3 of Brugia also induces the expansion of a population of CD4 cells that express CD25 and cytotoxic-T-lymphocyte-associated antigen 4 in an IL-4-independent fashion. By quantitative reverse transcription-PCR, we show that the CD25+ population is highly enriched in mRNA for the Foxp3 transcription factor and that these cells express significantly more IL-10 mRNA than the CD25- population, suggesting a likely regulatory phenotype. The functional capacity of these cells was demonstrated using a neutralizing CD25 monoclonal antibody (MAb). Mice treated with this MAb demonstrated elevated levels of antigen (Ag)-specific proliferation in vitro, and levels of Ag-specific Th2 cytokines were significantly increased. These results suggest a complex network of regulation in L3-infected mice with Th2 cells limiting the Th1 response, while T-regulatory cells modulate Th2 responses.

Animals↗

PubMed2006

Human CD4+CD25high regulatory T cells modulate myeloid but not plasmacytoid dendritic cells activation.

Human CD4(+)CD25(+) regulatory T cells (Treg) play an essential role in the prevention of autoimmune diseases. However, the mechanisms of immune suppression and the spectrum of cells they target in vivo remain incompletely defined. In particular, although Treg directly suppress conventional T cells in vitro, they have been shown to inhibit the Ag-presenting functions of macrophage- and monocyte-derived dendritic cells (DC). We have now studied the maturation of human blood-derived myeloid DC and plasmacytoid DC activated with TLR ligands in the presence of Treg. Preactivated Treg suppressed strongly TLR-triggered myeloid DC maturation, as judged by the blocking of costimulatory molecule up-regulation and the inhibition of proinflammatory cytokines secretion that resulted in poor Ag presentation capacity. Although IL-10 played a prominent role in inhibiting cytokines secretion, suppression of phenotypic maturation required cell-cell contact and was independent of TGF-beta and CTLA-4. In contrast, the acquisition of maturation markers and production of cytokines by plasmacytoid DC triggered with TLR ligands were insensitive to regulatory T cells. Therefore, human Treg may enlist myeloid, but not plasmacytoid DC for the initiation and the amplification of tolerance in vivo by restraining their maturation after TLR stimulation.

Antigen Presentation↗

PubMed1996

Myosin regulatory light chain modulates the Ca2+ dependence of the kinetics of tension development in skeletal muscle fibers.

To determine the role of myosin regulatory light chain (RLC) in modulating contraction in skeletal muscle, we examined the rate of tension development in bundles of skinned skeletal muscle fibers as a function of the level of Ca(2+) activation after UV flash-induced release of Ca(2+) from the photosensitive Ca(2+) chelator DM-nitrophen. In control fiber bundles, the rate of tension development was highly dependent on the concentration of activator Ca(2+) after the flash. There was a greater than twofold increase in the rate of tension development when the post-flash [Ca(2+)] was increased from the lowest level tested (which produced a steady tension that was 42% of maximum tension) to the highest level (producing 97% of maximum tension). However, when 40-70% of endogenous myosin RLC was extracted from the fiber bundles, tension developed at the maximum rate, regardless of the post-flash concentration of Ca(2+). Thus, the Ca(2+) dependence of the rate of tension development was eliminated by partial extraction of myosin RLC, an effect that was partially reversed by recombination of RLC back into the fiber bundles. The elimination of the Ca(2+) dependence of the kinetics of tension development was specific to the extraction of RLC rather than an artifact of the co-extraction of both RLC and Troponin C, because the rate of tension development was still Ca(2+) dependent, even when nearly 50% of endogenous Troponin C was extracted from fiber bundles fully replete with RLC. Thus, myosin RLC appears to be a key component in modulating Ca(2+) sensitive cross-bridge transitions that limit the rate of force development after photorelease of Ca(2+) in skeletal muscle fibers.

Animals↗

PubMed1994

Modulation of transcriptional regulatory properties of p53 by HPV E6.

The E6 protein encoded by human papillomavirus type 16 (HPV16), a genital virus with oncogenic potential, can target cellular p53 for rapid degradation following the formation of a complex including the two proteins. Some studies suggest that the E6 proteins encoded by HPV6 and 11, viral types which are normally limited to benign lesions, may also interact with p53, although the association is weaker than that seen with HPV16 E6. The present study demonstrates that E6 proteins from HPV16 and HPV6 can modulate the transcriptional regulatory functions of p53 in several cell types. A series of E6 mutants was used to show that association between E6 and p53 is necessary for this activity and that E6 proteins which retain the ability to associate with p53 but show no detectable degradation activity in vitro can, to some extent, abrogate p53 mediated transcriptional trans-regulation. This activity is augmented, however, by the ability of the E6 protein to target bound p53 for rapid degradation. These results suggest that some degree of modulation of p53 function is necessary in the normal viral life cycle but also demonstrate a correlation between the efficiency of this activity and oncogenic potential of the virus.

3T3 Cells↗

PubMed2006

Regulatory dendritic cells modulate immune responses via induction of T-cell apoptotic death.

We describe a regulatory lymphoid dendritic cell (LDC) population propagated from mouse liver nonparenchymal cells (NPC) in IL-3 and anti-CD40 monoclonal antibody that are phenotypically mature, and induce T-cell hyporesponsiveness by promoting T-cell apoptotic death, which is partially caspase-dependent, but is unlikely to be mediated by soluble factor(s). In vivo administration of liver LDC significantly prolonged the survival of vascularized cardiac allografts in an alloantigen-specific manner. This is associated with enhanced T-cell death in secondary lymphoid organs.

Animals↗

PubMed1995

Regulatory peptides as modulators of vagal influence on cardiac rhythm.

When the right vagus nerve of anesthetized cats was stimulated with repetitive bursts of pulses, decelerated heart rate became synchronized to the rhythm of the vagal bursts. Each burst applied to the vagus was followed by a single heart contraction. Within defined limits an increase in the frequency of vagal bursts evoked a proportional acceleration of the heart, whereas a decreased frequency diminished the heart rate. Therefore, over the range of synchronization the heart rate was precisely controlled by changing the vagal stimulation rate. We concluded that the chronotropic effect evoked by vagal bursts was composed of two functionally different types of influence, namely, inhibitory tonic and synchronizing. The vagotropic influence of intravenously injected regulatory peptides was found to be selective for either the tonic or synchronizing component. For instance, dalargin (D-Ala2-Leu5-Arg6-enkephalin) and neokyotorphin selectively diminished the inhibitory tonic vagal influence, whereas delta sleep inducing peptide and neurotensin potentiated it. The magnitude of synchronizing vagal influence was not modified by these peptides. In contrast, secretin selectively inhibited the synchronizing vagal effect, but the tonic one was not affected. Somatostatin potentiated the synchronizing effect but diminished the tonic one. These data support the hypothesis that certain regulatory peptides can modulate the effects of repetitive vagal bursts on pacemaker activity.

Animals↗

PubMed2005

Valproic acid inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in human thyroid cancer cells.

BACKGROUND: Among the most promising new therapies for thyroid cancer are the histone deacetylase inhibitors. Valproic acid (VA) is an anticonvulsant that inhibits histone deacetylase activity at nontoxic concentrations. We hypothesized that VA would have antineoplastic effects on human thyroid cancer cells. METHODS: We treated 1 papillary and 3 follicular thyroid cancer cell lines with VA (0.5-2 mmol/L) for 24 to 72 hours. Cell proliferation was measured with a cell proliferation assay kit. Annexin V-fluorescein isothiocyanate was used to quantitate cells that were undergoing apoptosis. Quantitative polymerase chain reaction was used to measure expression of apoptosis-regulatory and differentiation genes. RESULTS: VA inhibited growth in all cell lines by 26% to 59% at 48 hours and up to 77% at 72 hours. Nineteen percent to 30% of VA-treated cells underwent apoptosis, compared with 4% to 8% of the control cells. Expression of pro survival genes bcl-2 and bcl-xl was down-regulated by 10% to 60%; expression of the proapoptosis gene bax was up-regulated by 23% to 85%. Sodium-iodide symporter and thyroglobulin messenger RNA expression were up-regulated by 93% to 370% in follicular cell lines but remained unchanged in the papillary cell line. CONCLUSION: VA inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in thyroid cancer cells. These findings suggest that VA may be useful clinically for patients with thyroid cancers of follicular cell origin.

Adenocarcinoma, Follicular↗

PubMed2006

CD4+ CD25+ regulatory T cells modulate the T-cell and antibody responses in helicobacter-infected BALB/c mice.

Gastric Helicobacter spp. induce chronic gastritis that may lead to ulceration and dysplasia. The host elicits a T helper 1 (Th1) response that is fundamental to the pathogenesis of these bacteria. We analyzed immune responses in Helicobacter-infected, normal mice depleted of CD4+ CD25+ T cells to investigate the in vivo role of regulatory T cells (Tregs) in the modulation of Helicobacter immunopathology. BALB/c and transgenic mice were depleted of CD4+ CD25+ T cells by administration of an anti-CD25 antibody either at the time of infection with Helicobacter or during chronic infection and gastritis. Depletion of CD25+ Tregs prior to and during infection of mice with Helicobacter spp. did not affect either bacterial colonization or severity of gastritis. Depletion of CD25+ Tregs was associated with increased Helicobacter-specific antibody levels and an altered isotype distribution. Paragastric lymph node cells from CD25+ Treg-depleted and control infected mice showed similar proliferation to Helicobacter antigens, but only cells from anti-CD25-treated animals secreted Th2 cytokines. CD25+ Tregs do not control the level of gastritis induced by gastric Helicobacter spp. in normal, thymus-intact BALB/c mice. However, CD25+ Tregs influence the cytokine and antibody responses induced by infection. Autoimmune gastritis is not induced in Helicobacter-infected mice depleted of CD25+ Tregs but is induced in CD25+ Treg-depleted mice, which have a higher frequency of autoreactive T cells.

Animals↗

PubMed2000

Expression and modulation of apoptosis regulatory molecules in human melanocytes: significance in vitiligo.

Although the aetiology of the hypopigmentary disorder vitiligo is ill understood, it is clear that pigment producing cells are absent from vitiliginous lesional skin. The present study was designed to investigate the possible role of melanocyte-expressed apoptosis regulatory molecules in melanocyte disappearance. Flow cytometric evaluation of p53, p21, Bcl-2 and Bax revealed no differences in in vitro expression levels between normal control and non-lesional melanocytes. Moreover, no in situ immunohistological differences were observed in melanocytes present in control, non-lesional and perilesional skin. However, an enhanced number of p53+ nuclei, in the absence of detectable p21 expression, was detected in involved areas. The observed p53 expression pattern did not involve melanocytes and could be the result of ultraviolet (UV) A irradiation. Further, we showed that UVB is capable of modulating melanocyte-expressed apoptosis regulatory molecules. Consequently, a lethal dose of UVB was given to two groups of cultured normal control and non-lesional melanocytes. No significant differences were found when comparing the percentages and kinetics of UVB-induced apoptosis in these groups. In conclusion, our results indicate that the relative apoptosis susceptibility of melanocytes in vitiligo is comparable with that of normal control cells. It is therefore unlikely that vitiligo is causally related to dysregulation of apoptosis regulatory molecules.

Apoptosis↗

PubMed2003

Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery.

Several epidemiological studies have demonstrated that vitamin E is a chemopreventative agent for prostate cancer. alpha-Tocopheryl succinate (VES), a derivative of vitamin E, effectively modulates prostate cancer cell growth. However, little is known about the mechanisms regarding this action. Here we show that VES causes human prostate cancer cell LNCaP arrest at G1 phase. This effect is accomplished through VES significantly decreasing expression of the cell cycle regulatory proteins cyclin D1, D3, and E, cdk2 and 4, but not cdk6. Furthermore, VES reduces cdk4 kinase activity, Rb phosphorylation, and cyclin E mRNA expression. Recently there is increasing interest in the protective effect of the VES and selenium combination on prostate cancer. Here we show that VES and selenium work through different mechanisms to exert their inhibitory effects on prostate cancer cells. Taken together, our studies suggest that VES-mediated prostate cancer cell G1/S arrest is a consequence of the regulation of multiple molecules of the cell cycle regulatory machinery.

Anticarcinogenic Agents↗

PubMed2004

Tolerogenic APC generate CD8+ T regulatory cells that modulate pulmonary interstitial fibrosis.

Transforming growth factor-beta2-treated Ag-pulsed APC mimic APC from the immune privileged eye, and provide signals that generate regulatory T (Tr) cells and mediate peripheral tolerance. We postulated that TGF-beta2-treated Ag-pulsed APC (tolerogenic APC (tol-APC)) might also orchestrate regulation of immune mediated pathogenesis in nonimmune privileged tissues such as the lung. We used an adoptive transfer model of autoimmune pulmonary interstitial fibrosis called hapten immune pulmonary interstitial fibrosis (ADT-HIPIF) in this study. Mice that received 2,4,6-trinitrobenzene sulfonic acid-sensitized cells and challenged (intratracheally) with the hapten developed pulmonary interstitial fibrosis. However, transfer (i.v.) of TGF-beta2-treated 2,4,6-trinitrobenzene sulfonic acid-pulsed bone marrow-derived APC (tol-APC) to experimental mice 1 day after intratracheal challenge reduced the collagen deposition in the interstitium of the lung that usually follows challenge. Furthermore, ADT-HIPIF mice that received tol-APC developed Ag-specific efferent CD8+ Tr cells. Adoptive transfer of the Tr cells to another set of presensitized mice mediated suppression of the efferent phase of Th1 immune response and the subsequent immune dependent pulmonary interstitial fibrosis. Thus, tol-APC induced efferent CD8+ Tr cells in immune mice, and the regulation of the immune response limited the development of autoimmune pulmonary fibrosis in sensitized and pulmonary-challenged mice. Because ADT-HIPIF shares etiological and pathological characteristics with a variety of human immune inflammatory conditions in the lung that eventuate into interstitial fibrosis, these studies provide insight into potential therapy to alter the course of pulmonary fibrosis in humans.

Adoptive Transfer↗

PubMed2006

Transcriptional regulation by competing transcription factor modules.

Gene regulatory networks lie at the heart of cellular computation. In these networks, intracellular and extracellular signals are integrated by transcription factors, which control the expression of transcription units by binding to cis-regulatory regions on the DNA. The designs of both eukaryotic and prokaryotic cis-regulatory regions are usually highly complex. They frequently consist of both repetitive and overlapping transcription factor binding sites. To unravel the design principles of these promoter architectures, we have designed in silico prokaryotic transcriptional logic gates with predefined input-output relations using an evolutionary algorithm. The resulting cis-regulatory designs are often composed of modules that consist of tandem arrays of binding sites to which the transcription factors bind cooperatively. Moreover, these modules often overlap with each other, leading to competition between them. Our analysis thus identifies a new signal integration motif that is based upon the interplay between intramodular cooperativity and intermodular competition. We show that this signal integration mechanism drastically enhances the capacity of cis-regulatory domains to integrate signals. Our results provide a possible explanation for the complexity of promoter architectures and could be used for the rational design of synthetic gene circuits.

Algorithms↗

PubMed2000

Phosphorylation of CorS and CorR, regulatory proteins that modulate production of the phytotoxin coronatine in Pseudomonas syringae.

Production of the phytotoxin coronatine (COR) in Pseudomonas syringae pv. glycinea PG4180 is controlled by a modified two-component regulatory system consisting of three genes, corR, corP, and corS. CorR and CorP show similarity to response regulators, and CorS is related to histidine protein kinases that function as environmental sensors. In this study, CorR, CorP and the cytoplasmic portion of CorS, designated CorSDelta, were overproduced in P. syringae as translational fusions to the maltose-binding protein and purified by affinity chromatography. Autophosphorylation of CorSDelta was demonstrated when [gamma-(32)P]ATP was used as a phosphodonor. Phosphorylated CorSDelta (CorSDelta approximately P) was stable under basic conditions, but extremely sensitive when the pH was reduced, which is consistent with phosphorylation at a histidine residue. CorSDelta approximately P transferred its phosphoryl group to CorR but not to CorP, which correlates with the presence of a receiver aspartate residue in the former but not the latter protein. These results indicate that CorS functions as a histidine protein kinase and transphosphorylates CorR, a positive activator of cor gene transcription.

Amino Acids↗

PubMed2006

Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity.

The activities of intracellular receptors are regulated by their cognate ligands. Here we show that a series of related arylpyrazole compounds, which specifically bind the glucocorticoid receptor (GR), selectively modulated GR-regulated biological functions in preadipocyte, pre-osteoblast, and lung epithelial cell lines. Indeed, when we monitored 17 endogenous GR target genes in one of these cell types, we found that distinct arylpyrazole compounds induced different expression patterns. We showed by chromatin immunoprecipitation that the arylpyrazole compounds regulated, in a gene-specific manner, either GR occupancy of the genomic glucocorticoid response element (GRE) or events after GR association, such as histone modification. Overall, our results establish that subtle differences in ligand chemistry can profoundly influence the transcriptional regulatory activity of GR, and that endogenous genes bearing natural GREs are especially sensitive detectors of these differences.

3T3-L1 Cells↗

PubMed1986

Depletion of cellular ATP inhibits Na+/H+ antiport in cultured human cells. Modulation of the regulatory effect of intracellular protons on the antiporter activity.

The metabolic energy dependency of Na+/H+ exchange activity was investigated in cultured human A431 carcinoma cells and foreskin fibroblasts. Following the activation of Na+/H+ exchange which results from loading cells with Na+ or Li+, depletion of cellular ATP by incubation with metabolic inhibitors causes an inhibition of Na+/H+ exchange activity. This inhibition is reversible and correlates with the extent of the reduction in the ATP pool. On the other hand, reduction of the intracellular pH (pHi) to approximately 6.0-6.2 results in a similar effective activation of Na+/H+ exchange in both control and ATP-depleted cells. Na+/H+ exchange activity in ATP-depleted cells that either have or have not been loaded with Na+ shows a steep dependency on pHi, being essentially abolished above pHi of 6.4-6.5, whereas control cells show a considerable activity also at more alkaline pHi values. Thus, Na+/H+ exchange activity in ATP-depleted cells shows an increased dependency on intracellular protons. These findings suggest that although metabolic energy is not required as a driving force for Na+/H+ antiport, depletion of metabolic energy substrates inhibits the antiporter activity due to a modulation of an intracellular proton-dependent regulatory mechanism.

Adenosine Triphosphate↗

PubMed1996

Modulation of iron regulatory protein functions. Further insights into the role of nitrogen- and oxygen-derived reactive species.

Iron regulatory protein (IRP) is a cytosolic bifunctional [Fe-S] protein which exhibits aconitase activity or binds iron responsive elements (IREs) in untranslated regions of specific mRNA. The modulators of these activities are the intracellular concentration of iron and, as recently described, NO synthase activity. In this study, we attempted to establish in in vitro experiments whether peroxynitrite (ONOO-, the product of the reaction between NO and O2-.), as well as oxygen-derived radicals (O2-. and H2O2) and various NO donors, allow IRP to bind IREs using cytosol extract of macrophagelike RAW 264.7 cells. Neither the addition of a bolus of ONOO- or H2O2 nor O2-. generation significantly affected IRE binding even though they inhibited its aconitase activity. Moreover, we show that 3-morpholinosydnonimine (SIN-1), a chemical which releases both NO and O2-. enhanced IRE binding activity of IRP only in the presence of superoxide dismutase (SOD). S-Nitrosothiols and the NONOate sper/NO plus gluthathione (GSH) activated IRE binding by IRP whereas oxyhemoglobin prevented enhancement of this binding by SIN-1/SOD and sper/NO plus GSH. cis-Aconitate, substrate, also abolished the effect of SIN-1/SOD on IRE binding by IRP. These results imply that neither O2-. nor ONOO- can convert [4Fe-4S] IRP into IRE-binding protein but rather suggest that an active redox form of NO converts IRP into its IRE binding form by targeting the [Fe-S] cluster.

Aconitate Hydratase↗

PubMed2006

Specific phosphorylation of p120-catenin regulatory domain differently modulates its binding to RhoA.

p120-catenin is an adherens junction-associated protein that controls E-cadherin function and stability. p120-catenin also binds intracellular proteins, such as the small GTPase RhoA. In this paper, we identify the p120-catenin N-terminal regulatory domain as the docking site for RhoA. Moreover, we demonstrate that the binding of RhoA to p120-catenin is tightly controlled by the Src family-dependent phosphorylation of p120-catenin on tyrosine residues. The phosphorylation induced by Src and Fyn tyrosine kinases on p120-catenin induces opposite effects on RhoA binding. Fyn, by phosphorylating a residue located in the regulatory domain of p120-catenin (Tyr112), inhibits the interaction of this protein with RhoA. By contrast, the phosphorylation of Tyr217 and Tyr228 by Src promotes a better affinity of p120-catenin towards RhoA. In agreement with these biochemical data, results obtained in cell lines support the important role of these phosphorylation sites in the regulation of RhoA activity by p120-catenin. Taken together, these observations uncover a new regulatory mechanism acting on p120-catenin that contributes to the fine-tuned regulation of the RhoA pathways during specific signaling events.

Adaptor Proteins, Signal Transducing↗