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PubMed2002

Interactions between regulatory and catalytic subunits of the Candida albicans cAMP-dependent protein kinase are modulated by autophosphorylation of the regulatory subunit.

The cAMP-dependent protein kinase (PKA) from Candida albicans is a tetramer composed of two catalytic subunits (C) and two type II regulatory subunits (R). To evaluate the role of a putative autophosphorylation site of the R subunit (Ser(180)) in the interaction with C, this site was mutated to an Ala residue. Recombinant wild-type and mutant forms of the R subunit were expressed in Escherichia coli and purified. The wild-type recombinant R subunit was fully phosphorylated by the purified C subunit, while the mutant form was not, confirming that Ser(180) is the target for the autophosphorylation reaction. Association and dissociation experiments conducted with both recombinant R subunits and purified C subunit showed that intramolecular phosphorylation of the R subunit led to a decreased affinity for C. This diminished affinity was reflected by an 8-fold increase in the concentration of R subunit needed to reach half-maximal inhibition of the kinase activity and in a 5-fold decrease in the cAMP concentration necessary to obtain half-maximal dissociation of the reconstituted holoenzyme. Dissociation of the mutant holoenzyme by cAMP was not affected by the presence of MgATP. Metabolic labeling of yeast cells with [(32)P]orthophosphate indicated that the R subunit exists as a serine phosphorylated protein. The possible involvement of R subunit autophosphorylation in modulating C. albicans PKA activity in vivo is discussed.

Binding Sites↗

PubMed2003

Angiotensin II type 1 receptor blockade prevents diastolic heart failure through modulation of Ca(2+) regulatory proteins and extracellular matrix.

BACKGROUND: Angiotensin II type 1 receptor (AT(1)R) blockade attenuates left ventricular relaxation abnormality and myocardial stiffening in a model of hypertensive diastolic heart failure, but the mechanisms remain unclear. OBJECTIVE: To test the hypothesis that such benefits are provided by modulation of the quantitative or qualitative changes, or both, in Ca2+ regulatory proteins and extracellular matrix. DESIGN AND METHODS: Dahl salt-sensitive rats fed a diet containing 8% sodium chloride from 7 weeks of age present pulmonary congestion as a result of diastolic dysfunction with preserved systolic function, around 20 weeks of age. In this study, animals of this model were divided into groups that received (n = 7) or did not receive (n = 6) a subdepressor dose of an AT(1)R antagonist (candesartan cilexetil) from 8 weeks of age. RESULTS: Long-term AT(1)R blockade prevented the development of diastolic heart failure through attenuation of left ventricular relaxation abnormality and myocardial stiffening without a reduction in blood pressure. Left ventricular relaxation abnormality was not associated with any change in the ratio of abundance of phospholamban to that of sarcoplasmic reticulum Ca2+-ATPase 2a protein, but was accompanied by a decrease in Ser16-phosphorylated phospholamban. The AT(1)R blockade inhibited this decrease. Attenuation in myocardial stiffening was associated with reduced tissue collagen content, attenuated collagen cross-linking, and suppressed gene expression of collagen type I rather than type III. CONCLUSIONS: AT(1)R blockade prevented abnormal relaxation at least partly through functional alterations in Ca2+-handling proteins in a hypertensive model of diastolic heart failure. It attenuated myocardial stiffening through preventing a shift in the phenotype of collagen synthesized and the accumulation of cross-linked collagen. These beneficial effects of AT(1)R blockade in diastolic heart failure are achieved without a reduction in blood pressure.

Angiotensin Receptor Antagonists↗

PubMed2001

Stage-specific modulation of IFN-regulatory factor 4 function by Krüppel-type zinc finger proteins.

Optimal humoral responses depend on the activation of Ag-specific B cells, followed by their progression toward a fully differentiated phenotype. Acquisition of stage-appropriate patterns of gene expression is crucial to this differentiation program. However, the molecular mechanisms used by B cells to modulate gene expression as they complete their maturation program are poorly understood. IFN-regulatory factor 4 (IRF-4) plays a critical role in mature B cell function. Using the transcriptional regulation of the human B cell activation marker CD23 as a model system, we have previously demonstrated that IRF-4 is induced in response to B cell-activating stimuli and that it acts as a transactivator of CD23 gene expression. We have furthermore found that IRF-4 function can be blocked by B cell lymphomas 6 (BCL-6) protein, a Krüppel-type zinc finger repressor normally expressed in germinal center B cells. However, CD23 expression is known to be down-regulated in plasma cells despite high level expression of IRF-4 and the lack of BCL-6, suggesting that in plasma cells the IRF-4-mediated induction of CD23 is prevented by its interaction with a distinct repressor. In this set of studies, we demonstrate that IRF-4 interacts with B lymphocyte-induced maturation protein/positive regulatory domain I-binding factor 1 (Blimp1/PRD1-BF1), a Krüppel-type zinc finger protein whose expression correlates with terminal B cell differentiation. Functional studies indicate that Blimp1, like BCL-6, can block IRF-4-transactivating ability. These findings thus support a model whereby IRF-4 function is modulated in a stage-specific manner by its interaction with developmentally restricted sets of Krüppel-type zinc finger proteins.

Binding Sites↗

PubMed2002

The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage.

Iron acquisition is a fundamental requirement for many aspects of life, but excess iron may result in formation of free radicals that damage cellular constituents. For this reason, the amount of iron within the cell is carefully regulated in order to provide an adequate level of a micronutrient while preventing its accumulation and toxicity. A major mechanism for the regulation of iron homeostasis relies on the post-transcriptional control of ferritin and transferrin receptor mRNAs, which are recognized by two cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) that modulate their translation and stability, respectively. IRP-1 can function as a mRNA binding protein or as an aconitase, depending on whether it disassembles or assembles an iron-sulfur cluster in response to iron deficiency or abundancy, respectively. IRP-2 is structurally and functionally similar to IRP-1, but does not assemble a cluster nor exhibits aconitase activity. Here we briefly review the role of IRP in iron-mediated damage induced by oxygen radicals, nitrogen-centered reactive species, and xenobiotics of pharmacological and clinical interest.

Aconitate Hydratase↗

PubMed2003

REDUCE: An online tool for inferring cis-regulatory elements and transcriptional module activities from microarray data.

REDUCE is a motif-based regression method for microarray analysis. The only required inputs are (i) a single genome-wide set of absolute or relative mRNA abundances and (ii) the DNA sequence of the regulatory region associated with each gene that is probed. Currently supported organisms are yeast, worm and fly; it is an open question whether in its current incarnation our approach can be used for mouse or human. REDUCE uses unbiased statistics to identify oligonucleotide motifs whose occurrence in the regulatory region of a gene correlates with the level of mRNA expression. Regression analysis is used to infer the activity of the transcriptional module associated with each motif. REDUCE is available online at http://bussemaker.bio.columbia.edu/reduce/. This web site provides functionality for the upload and management of microarray data. REDUCE analysis results can be viewed and downloaded, and optionally be shared with other users or made publicly accessible.

Algorithms↗

PubMed1985

Effects of granuloma modulation induced by regulatory-T-lymphocyte activity on angiotensin II/III production by granuloma macrophages in murine schistosomiasis mansoni.

Angiotensins are produced by granuloma macrophages in murine Schistosoma mansoni. During the course of infection, granuloma undergo a T-cell-dependent process called modulation in which their maximal size decreases. This study was undertaken to establish whether angiotensin production by granuloma macrophages is altered by immunoregulatory lymphocytes. Granuloma macrophages from modulated lesions released and contained more angiotensin II/III (AII/III) and less angiotensin I (AI) than those from the acute infection. Captopril, a specific angiotensin-converting-enzyme (ACE) inhibitor, appreciably decreased AII/III produced by macrophages from modulated granulomas. Adoptive transfer of splenic T lymphocytes from chronically infected donors into acutely infected recipients altered angiotensin production by the granuloma macrophages in a manner similar to that seen in modulated lesions. However, no difference was detected in the capacity of granuloma macrophages from acutely or chronically infected mice to metabolize 125I-AI or -AII added to cell cultures. Similarly, captopril did not alter the metabolism of exogenously administrated angiotensins. These findings suggest that regulatory T lymphocytes influence the metabolism by granuloma macrophages of endogenously produced angiotensins at least in part by induction of macrophage ACE activity. However, the degradation of extracellular AI and AII may result from the activity of enzymes other than ACE which are not inducible by modulation.

Angiotensin II↗

PubMed2006

Therapeutic modulation of cutaneous autoimmunity by regulatory T cells.

Cutaneous autoimmunity is characterized by the presence of autoantibodies and/or autoreactive T cells. Several mechanisms have been developed to avoid loss of immunotolerance to self such as activation-induced cell death, deletion, ignorance and active suppression of autoreactivity. Regulatory ('suppressor') T cells play a pivotal role in inhibiting the activation and function of effector T cells. CD4(+)CD25(+) T cells constitute a subset of regulatory T cells, which have been shown to suppress the development of organ-specific autoimmunity in mice. Recent understanding in the generation and function of human regulatory T cells indicates that these cells are involved in the appearance of inflammatory as well as bullous autoimmune dermatosis. These findings suggest that modulation of regulatory T cell numbers or function might be a promising therapeutic alternative for the treatment of such disorders. In the following, recent strategies aimed at inducing antigen-specific or non-specific regulatory T cells for the immunotherapy of ongoing cutaneous autoimmunity are presented and discussed. Hopefully, pursuing these strategies in the future will result in the initiation of randomized clinical studies analysing the usefulness of regulatory T cells for human skin diseases in great detail.

Animals↗

PubMed1975

The mitochondrial malic enzymes. I. Submitochondrial localization and purification and properties of the NAD(P)+-dependent enzyme from adrenal cortex.

Rat and calf adrenal cortex homogenates were found to contain three different malic enzymes. Two were strictly NADP+-dependent and were localized, one each, in the cytosol and the mitochondrial fractions, respectively. These two enzymes appear to be identical to those described by Simpson and Estabrook (Simpson, E. R., and Estabrook, R. W. (1969) Arch. Biochem. Biophys. 129, 384-395). The third was NAD(P)+-linked and was present in the mitochondrial fraction only. All three malic enzymes separated as distinct bands during electrophoresis on 5 percent polyacrylamide slab gels at pH 9.0. Marker enzymes and the mitochondrial malic enzymes migrated together in intact mitochondria during sucrose density gradient centrifugations despite changes in the equilibrium position of the mitochondria promoted by energy-dependent calcium phosphate accumulation. In adrenal cortex mitochondria subfractionated by the method of Sottocasa et al. (SOTTOCASA, G.L., KUYLENSTIERNA, B., ERNSTER, L., and BERGSTAND, A. (1967) J. Cell Biol. 32, 415-438), both malic enzymes were associated with the inner membrane-matrix space. Sonication solubilized the two malic enzymes along with the matrix space marker enzymes. The NAD(P)+-dependent malic enzyme was purified 100-fold from calf adrenal cortex mitochondria. The final preparation was free of malic dehydrogenase, fumarase, the strictly NADP+-linked malic enzyme and adenylate kinase. Either Mn24 orMg2+ was required for activity and 1 mol of pyruvate was formed for each mole of NAD+ and NADP+ reduced. The pH optima with NAD+ and NADP+ were 6.5 tp 7.0 and 6.0 to 6.5, respectively. Michaelis-Menten kinetics were observed on the alkaline side. Fumarate, succinate, and isocitrate were positive and ATP and ADP were negative modulators of the regulatory enzyme. The modulators did not influence the stoichiometry and they were not metabolized during the reaction. Under Vmax conditions the ratios for the rate of NAD+:NADP+ reduction were 1.76 and 1.15 at pH 7.4 and 6.0, respectively. The apparent Michaelis constants also differed depending on the pH and the coenzyme. At pH 7.4 (in the presence of 5 mM fumarate) and at pH 6.0 (no fumarate) the Km values for (-)-malate, NAD+, and Mn2+ were 1.7, 0.16, and 0.15 mM, and 0.31, 0.06, and 0.09 mM, respectively. At pH 7.4 (5MM fumarate) and pH 6.0 (no fumarate), the Km values for (-)-malate, NADP+, and Mn2+ were 6.5, 0.62, and 0.59 mM, and 0.68. 0.12, and 0.31 mM, respectively. The apparent Ki values for ATP with NAD+ and NADP+ as coenzyme were 0.42 and 0.27 mM, respectively.

Adrenal Cortex↗

PubMed2006

An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes.

CD4+CD25+Foxp3+ regulatory T lymphocytes are crucial for maintenance of immunological tolerance to self and innocuous non-self, are known to modulate immunity to tumors and infectious agents and can induce transplantation tolerance. Surprisingly, only a single genetic polymorphism is known to modulate regulatory T cell (Treg) development in the thymus, leading to a lethal autoimmune disorder. Here, we show that considerably different levels of Tregs are found in the thymi of distinct common laboratory mouse strains. We demonstrate that distinct levels of phenotypically and functionally identical Tregs develop with similar kinetics in the studied mice, that the responsible locus acts in a thymocyte-intrinsic manner and that levels of thymic Foxp3+ Tregs correlate to those found in the periphery. Using several congenic mouse strains, we mapped one of the at least two genetic loci capable of quantitatively modulating thymic Treg development to a <or=2.2 Mb region telomeric to the MHC. Our data indicate that polymorphic genes closely linked to the MHC locus substantially modulate differentiation of Tregs. Identification of responsible genes should help in understanding the mechanisms involved in commitment to the Treg lineage as well as selection of these cells in the thymus.

Animals↗

PubMed2001

Baicalein induces a dual growth arrest by modulating multiple cell cycle regulatory molecules.

Baicalein, a flavonoid present in the root of Scutellaria baicalensis Georgi, has been reported to inhibit cell proliferation in several types of cells. In this study, the effect of baicalein on cell growth and the mechanism of growth modulation were examined in primary cultured rat heart endothelial cells. Here, we report that treatment with 100-microM baicalein caused an almost complete inhibition of cell proliferation after 5 days of incubation. Baicalein mediated G1 and G2 growth arrest accompanied by the down-regulation of cyclin D2, cyclin A, cyclin-dependent kinase 1 (Cdk1) and cyclin-dependent kinase 2 (Cdk2), and up-regulation of p15(Ink4B), p21(CIP1/Waf1), p53 and cyclin E. Evaluation of the kinase activity of cyclin-Cdk complexes showed that baicalein decreased Cdk1, Cdk2, cyclin D2 and cyclin A expression in endothelial cells, leading to markedly reduced Cdk/cyclin-associated kinase activities. These results suggest that baicalein inhibits the proliferation of rat heart endothelial cells via G1 and G2 arrest in association with the down-regulation of the expression and function of Cdk1, Cdk2, cyclin D2 and cyclin A proteins, and up-regulation of cyclin E, p15(Ink4B), p53 and p21(CIP1/Waf1).

Animals↗

PubMed2001

Steroidogenic acute regulatory protein binds cholesterol and modulates mitochondrial membrane sterol domain dynamics.

The steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step of steroidogenesis, delivery of cholesterol to the inner mitochondrial membrane. However, the mechanism whereby cholesterol translocation is accomplished has not been resolved. Recombinant StAR proteins lacking the first N-terminal 62 amino acids comprising the mitochondrial-targeting sequence were used to determine if StAR binds cholesterol and alters mitochondrial membrane cholesterol domains to enhance sterol transfer. First, a fluorescent NBD-cholesterol binding assay revealed 2 sterol binding sites (K(d) values near 32 nm), whereas the inactive A218V N-62 StAR mutant had only a single binding site with 8-fold lower affinity. Second, NBD-cholesterol spectral shifts and fluorescence resonance energy transfer from StAR Trp residues to NBD-cholesterol showed (i) close molecular interaction between these molecules (R(2/3) = 33 A) and (ii) sensitized NBD-cholesterol emission from only one of the two sterol binding sites. Third, circular dichroism showed that cholesterol binding induced a change in StAR secondary structure. Fourth, a fluorescent sterol transfer assay that did not require separation of donor and acceptor mitochondrial membranes demonstrated that StAR enhanced mitochondrial sterol transfer as much as 100-fold and induced/increased the formation of rapidly transferable cholesterol domains in isolated mitochondrial membranes. StAR was 67-fold more effective in transferring cholesterol from mitochondria of steroidogenic MA-10 cells than from human fibroblast mitochondria. In contrast, sterol carrier protein-2 (SCP-2) was only 2.2-fold more effective in mediating sterol transfer from steroidogenic cell mitochondria. Taken together these data showed that StAR is a cholesterol-binding protein, preferentially enhances sterol transfer from steroidogenic cell mitochondria, and interacts with mitochondrial membranes to alter their sterol domain structure and dynamics.

4-Chloro-7-nitrobenzofurazan↗

PubMed1995

Retinoid X receptor-alpha and apolipoprotein AI regulatory protein 1 differentially modulate 3,5,3'-triiodothyronine-induced transcription.

The formation of heterodimers with thyroid hormone receptor (TR) and other nuclear hormone receptors on thyroid hormone response elements (TREs) is important for T3-regulated gene transcription. The potential roles of retinoid X receptor-alpha (RXR alpha) and apolipoprotein regulatory protein-1 (ARP-1) in T3-mediated transcription were studied on a well characterized TRE, a direct repeat of AGGTCA separated by four nucleotides (DR4), using electrophoretic mobility shift assays and transient transfection in CV-1 cells. It was shown that RXR alpha blocked liganded TR alpha-induced transcription. However, ARP-1 did not block T3/TR alpha-mediated transcription, although both TR alpha/RXR alpha and TR alpha/ARP-1 heterodimers had similar affinities for the TRE-DR4. In contrast, wild type ARP-1 reversed the blocking effect of RXR alpha on the liganded TR alpha-induced transcription, whereas a dimerization domain-deleted ARP-1 mutant (ARP-1 delta C) did not, suggesting that ARP-1 modulates T3-induced transcription through a dimerization process. Thus, the TRE-DR4 differentially responds to T3 at the transcriptional level by accommodating a battery of TR heterodimeric complexes.

Animals↗

PubMed1998

CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation.

Although CREB seems to be important for memory formation, it is not known which of the isoforms of CREB, CREM, or ATF1 are expressed in the neurons that undergo long-term synaptic changes and what roles they have in memory formation. We have found a single Aplysia CREB1 gene homologous to both mammalian CREB and CREM and have characterized in the sensory neurons that mediate gill-withdrawal reflex the expression and function of the three proteins that it encodes: CREB1a, CREB1b, and CREB1c. CREB1a is a transcriptional activator that is both necessary and, upon phosphorylation, sufficient for long-term facilitation. CREB1b is a repressor of long-term facilitation. Cytoplasmic CREB1c modulates both the short- and long-term facilitation. Thus, in the sensory neurons, CREB1 encodes a critical regulatory unit converting short- to long-term synaptic changes.

Amino Acid Sequence↗

PubMed2006

The diabetes type 1 locus Idd6 modulates activity of CD4+CD25+ regulatory T-cells.

The genetic locus Idd6 confers susceptibility to the spontaneous development of type 1 diabetes in the NOD mouse. Our studies on disease resistance of the congenic mouse strain NOD.C3H 6.VIII showed that Idd6 influences T-cell activities in the peripheral immune system and suggest that a major mechanism by which the Idd6 locus modifies diabetes development is via modulation of regulatory T-cell activities. Our transfer experiments using total splenocytes and purified T-cells demonstrated that the locus specifically controls the efficiency of disease protection mediated by the regulatory CD4(+)CD25(+) T-cell subset. Our data also implicate the Idd6 locus in controlling the balance between infiltrating lymphocytes and antigen-presenting cells within the pancreatic islet.

Aging↗

PubMed1996

[The neuronal theory and new concepts of the structure of the nervous system].

An analysis of neuron theory modern state was carried out on the base of data from literature and available material. The idea of anatomic, functional and biochemical polarity self-dependence of a neuron and its histochemical polarity have changed significantly. It is said to be confirmed that neuron does not work on its own, its trophics is impossible without glia and one neuron may contain not one but several mediators combined with modulators and regulatory neuropeptides. Postulates on the nervous system module organization seems to be the most well-grounded.

Animals↗

PubMed1999

Control of transferrin receptor expression via nitric oxide-mediated modulation of iron-regulatory protein 2.

Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). When iron in the intracellular transit pool is scarce, IRPs bind to iron-responsive elements (IREs) in the 5'-untranslated region of the ferritin mRNA and 3'-untranslated region of the transferrin receptor (TfR) mRNA. Such binding inhibits translation of ferritin mRNA and stabilizes the mRNA for TfR, whereas the opposite scenario develops when iron in the transit pool is plentiful. However, we (Richardson, D. R., Neumannova, V., Nagy, E., and Ponka, P. (1995) Blood 86, 3211-3219) and others reported that the binding of IRPs to IREs can also be modulated by nitric oxide (NO). In this study, we showed that a short exposure of RAW 264.7 cells (a murine macrophage cell line) to the NO(+) donor, sodium nitroprusside (SNP), caused a significant decrease in IRP-2 binding to the IREs followed by IRP-2 degradation and that these changes occurred without affecting IRP-1 binding. The SNP-mediated degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or lactacystin, known inhibitors of proteasome-dependent protein degradation. A SNP-mediated decrease in IRP-2 binding and levels was associated with a dramatic decrease in TfR mRNA levels and an increase in ferritin synthesis. Importantly, the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA levels. These observations suggest that IRP-2 can play an important role in controlling transferrin receptor expression.

Animals↗

PubMed2006

MicroRNA modulation of RNA-binding protein regulatory elements.

We propose that microRNAs could modulate RNA-binding protein binding sites in a dynamic manner. We suggest that the cis-regulatory code targeted by microRNAs is, at least in part, the same as that read by mRNA-binding proteins. Our hypothesis predicts that microRNAs indirectly or directly bind to RNA-binding protein binding sites. Alternatively, the microRNA-mRNA interactions can themselves be the target of an mRNA-binding protein. Lastly, we envision examples where multiple mRNA regulatory elements are simultaneously influenced by microRNA-mRNA interactions such that the binding of one or more microRNA results in conformational changes in the structure of the mRNA, thereby, either revealing or masking a second regulatory element.

Humans↗

PubMed2004

Activation of CRABS CLAW in the Nectaries and Carpels of Arabidopsis.

CRABS CLAW (CRC), a member of the YABBY gene family, is required for nectary and carpel development. To further understand CRC regulation in Arabidopsis thaliana, we performed phylogenetic footprinting analyses of 5' upstream regions of CRC orthologs from three Brassicaceae species, including Arabidopsis. Phylogenetic footprinting efficiently identified functionally important regulatory regions (modules), indicating that CRC expression is regulated by a combination of positive and negative regulatory elements in the modules. Within the conserved modules, we identified putative binding sites of LEAFY and MADS box proteins, and functional in vivo analyses revealed their importance for CRC expression. Both expression and genetic studies demonstrate that potential binding sites for MADS box proteins within the conserved regions are functionally significant for the transcriptional regulation of CRC in nectaries. We propose that in wild-type flowers, a combination of floral homeotic gene activities, specifically the B class genes APETALA3 and PISTILLATA and the C class gene AGAMOUS act redundantly with each other and in combination with SEPALLATA genes to activate CRC in the nectaries and carpels. In the absence of B and C class gene activities, other genes such as SHATTERPROOF1/2 can substitute if they are ectopically expressed, as in an A class mutant background (apetala2). These MADS box proteins may provide general floral factors that must work in conjunction with specific factors in the activation of CRC in the nectaries and carpels.

AGAMOUS Protein, Arabidopsis↗