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PubMed2004

Crystallization and preliminary X-ray crystallographic analysis of the RecR protein from Deinococcus radiodurans, a member of the RecFOR DNA-repair pathway.

The RecR protein plays a key role in the RecFOR pathway of recombination, which is necessary for the repair of ssDNA gaps. RecR from Deinococcus radiodurans has been overexpressed in Escherichia coli and crystallized at 297 K using polyethylene glycol 1000 as a precipitant. X-ray diffraction data to 2.90 A resolution have been collected at 100 K using Cu Kalpha X-rays from a mercury-soaked crystal. The crystal belongs to space group C222(1), with unit-cell parameters a = 106.96, b = 122.25, c = 156.01 A. The asymmetric unit contains four monomers of RecR, with a crystal volume per protein weight (V(M)) of 2.57 A(3) Da(-1) and a solvent content of 51.0%.

Bacterial Proteins↗
PubMedDate not supplied

GA-binding protein transcription factor: a review of GABP as an integrator of intracellular signaling and protein-protein interactions.

GA-binding protein (GABP) is an ets transcription factor that controls gene expression in several important biological settings. It is unique among ets factors, since the transcriptionally active complex is an obligate heterotetramer that is composed of two distinct proteins. GABPalpha includes an ets DNA binding domain (DBD), while a distinct protein, GABPbeta, contains ankyrin repeats and the transcriptional activation domain (TAD). GABP was first identified as a regulator of viral genes and nuclear respiratory factors. However, GABP is now recognized to be a key transcriptional regulator of dynamically regulated, lineage-restricted genes, especially in myeloid cells and at the neuromuscular junction. Furthermore, it regulates genes that are intimately involved in cell cycle control, protein synthesis, and cellular metabolism. GABP acts as an integrator of cellular signaling pathways by regulating key hormones and transmembrane receptors. In addition, GABP itself, is a target of phosphorylation events that lie downstream of signal transduction pathways. The physical and functional interactions of GABPalpha and GABPbeta with each other and with other transcription factors and co-activators are key to its ability to regulate gene expression. Its role in regulating genes involved in fundamental cellular processes places GABP at the nexus of key cellular pathways and functions.

DNA-Binding Proteins↗
PubMed1999

Antigen receptor-mediated activation of extracellular related kinase (ERK) in B lymphocytes of teleost fishes.

In mammalian B lymphocytes, engagement of the B cell antigen receptor (BCR) activates several parallel intracellular signaling pathways which ultimately lead to expression of differentiated functions such as cell proliferation and antibody production or to cellular apoptosis. BCR engagement stimulates the classical mitogen activated protein kinase (MAPK) pathway, also called the extracellular-related kinase (ERK) pathway, resulting in activation of the signature terminal enzyme in the pathway, MAPK (or ERK). BCR signaling also activates the phosphatidyl inositol pathway and its key enzyme protein kinase C (PKC). To investigate the ERK pathway in cells of the teleost immune system, peripheral blood leukocytes from red drum or channel catfish were treated with PKC activators or antibodies which crosslink the BCR. Proteins were identified in both red drum and catfish B cells that resembled mammalian ERKs in molecular weight and in their possessing a distinctive pTEpY dual phosphorylation site. BCR-mediated activation of these presumptive teleost ERKs depended in part (red drum) or in total (catfish) on PKC. To our knowledge this represents the first report of a functional MAPK kinase pathway in teleost fish.

Animals↗
PubMed2001

Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1.

Multiple endocrine neoplasia type 1 (MEN1) is a rare but informative syndrome for endocrine tumorigenesis. Since its isolation, several groups have begun to determine the role of menin, the protein product of MEN1, in sporadic endocrine tumors as well as tumors of the MEN1 syndrome. Mutations of menin have been reported in more than 400 families and tumors, most of which are truncating mutations, thus supporting the function of menin as a tumor suppressor. The exact function of menin is unknown, but overexpression of menin inhibits proliferation of Ras-transformed NIH3T3 cells. Since menin interacts with proteins from both the TGF beta and AP-1 signaling pathways, perhaps its tumor suppressor function is related to these key cell growth pathways. In this review we will discuss the various clinical manifestations of MEN1 syndrome, potential mechanisms of MEN1 tumorigenesis, and mutations associated with MEN and sporadic endocrine tumors.

Amino Acid Sequence↗
PubMed2000

[Effect of temperature on the activity of some enzymes representative of EMP pathway and TCA cycle in psychrophilic yeast].

Some key enzymes of EMP pathway and TCA cycle in a psychrophilic yeast Y18 were studied in this paper compared with those of Saccharomyces cerevisiae. The results indicated that fructose, 1,6-bisphosphate aldolase, succinate dehydrogenase, and hexokinase in Y18 were very thermolabile and have high activity at low temperature. These enzymes belong to cold-active enzymes. Alpha-ketoglutarate dehydrogenase existed possibly in isoenzyme which had different temperature characteristics. Citrayl synthetase was very similar in temperature characteristics to that of mesophiles. The Km value of succinate dehydrogenase both from Y18 and S. cerevisiae were studied and Some features of enzyme in psychrophiles were also discussed in this paper.

Cryptococcus↗
PubMed1977

Effect of dietary protein level on some key enzymes of the tryptophan-NAD pathway.

1. Six groups of rats were given diets containing protein at three levels (50, 100 and 200 g/kg), with and without nicotinic acid. After 4 weeks on these diets some key enzymes of the tryptophan and nicotinic acid-NAD pathway, liver nicotinamide nucleotide concentration, and urinary metabolites of tryptophan and nicotinic acid were studied. 2. Liver nicotinamide nucleotide levels were lower in rats given the diet with 50 g protein/kg as compared to those in rats given diets with 100 and 200 g protein/kg. The addition of nicotinic acid to the diet resulted in a significant increase in the levels of nicotinamide nucleotides only in rats given 50 g protein/kg diet but not in those given either 100 or 200 g protein/kg diet. 3. Liver tryptophan oxygenase (EC 1.13.1.12) activity increased with increasing dietary protein level. Niconitic acid in the diet had no effect on its activity. 4. Quinolinate phosphoribosyltransferase (EC 2.4.2.a) activity in liver was inversely related to dietary protein level, and nicotinic acid in the diet had no effect on its activity. 5. Liver nicotinate phosphoribosyltransferase (EC 2.4.2.11) activity and kidney picolinate carboxylase (EC 4.1.1.45) activity were not altered either by dietary protein level or nicotinic acid in the diet. 6. The addition of nicotinic acid to the diet resulted in increased excretion of N'-methylnicotinamide at all dietary protein levels. 7. The inverse relationship between protein level in the diet and liver quinolinate phosphoribosyltransferase activity, the rate-limiting enzyme of the tryptophan-NAD pathway suggests that the efficiency of conversion of tryptophan to NAD is related to protein level in the diet, the efficiency decreasing with an increase in the level of dietary protein.

Animals↗
PubMed2006

Alpha-lipoic acid modulates ovarian surface epithelial cell growth.

OBJECTIVE: The intracellular redox state plays an important role in controlling inflammation. Clinical and laboratory data suggest that inflammation can lead to tumor progression. We hypothesized that restoring intracellular redox control would inhibit inflammation and subsequently tumor progression. Our studies were designed to investigate the effect of alpha-lipoic acid (ALA), a naturally occurring antioxidant, on a key inflammatory signaling pathway and cell proliferation in normal and tumorigenic ovarian surface epithelial cells. METHODS: Normal and tumorigenic ovarian surface epithelial cells were isolated as described by Roby and coworkers [Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawpik O, Persons DL, Smith PG, Terranova PF, Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogen 2000;21 (4):585. [1]]. The effect of ALA on cellular function was measured in cell proliferation and apoptosis assays. p27(kip1) protein levels were measured by Western analysis. Activation of NF-kappaB dependent transcription was assessed in cell cultures transiently transfected with NF-kappaB controlled reporter constructs. RESULTS: Our results reveal that ALA selectively inhibits the growth of tumorigenic as compared to non-tumorigenic ovarian surface epithelial cells. The growth inhibitory effect of ALA is not due to induction of apoptosis but instead is associated with an increase in the half-life of the cyclin-dependent kinase inhibitor, p27(kip1). In parallel to the growth inhibitory effect, ALA also affects a key inflammatory signaling pathway by inhibiting TNFalpha-induced NF-kappaB signaling activity. CONCLUSIONS: Our studies are the first to show that ALA treatment has a growth inhibitory effect on malignant surface epithelial cells of ovarian origin. We have also confirmed the reproducibility of the immunocompetent mouse ovarian cancer model originally described by Roby and coworkers [Roby KF, Taylor CC, Sweetwood JP, Cheng Y, Pace JL, Tawpik O, Persons DL, Smith PG, Terranova PF, Development of a syngeneic mouse model for events related to ovarian cancer. Carcinogen 2000;21 (4):585].

Animals↗
PubMed2002

Nuclear factor kappa B regulation of proinflammatory cytokines in human gestational tissues in vitro.

Proinflammatory cytokines are implicated in the initiation and progression of human labor and delivery, particularly in relation to infection-induced preterm labor. In nongestational tissues, the nuclear factor kappa B (NF-kappaB) transcription pathway is a key regulator of proinflammatory cytokine release. In these tissues, sulfasalazine (SASP), through its ability to inhibit NF-kappaB activation, inhibits release of interleukin (IL)-2, IL-12, and tumor necrosis factor (TNF)-alpha. Therefore, the aim of this study was to investigate whether or not NF-kappaB activation regulates the formation of proinflammatory cytokines in human gestational tissues. Human placenta, amnion, and choriodecidua (n = 9 separate placentas) were incubated with 10 microg/ml of lipopolysaccharide (LPS) in the absence (control) or presence of SASP (0.1, 1, 5, or 10 mM). After 6 h of incubation, the tissues were collected, and NF-kappaB DNA binding activity in nuclear extracts was assessed by electromobility shift binding assay. The incubation medium was collected and the release of IL-6, IL-8, and TNF-alpha was quantified by ELISA. Treatment of placenta, amnion, and choriodecidua with SASP at concentrations 5 mM or greater significantly inhibited the release of IL-6, IL-8, and TNF-alpha, and NF-kappaB activation (ANOVA, P < 0.05). The data presented in this study demonstrate that the NF-kappaB transcription pathway is a key regulator of LPS-stimulated IL-6, IL-8, and TNF-alpha release from human gestational tissues. The control of NF-kappaB activation may therefore provide an alternative therapeutic strategy for reducing the release of proinflammatory mediators in infection associated preterm labor.

Adult↗
PubMed2004

IkappaB kinases: key regulators of the NF-kappaB pathway.

The nuclear factor (NF)-kappaB pathway is important for the expression of a wide variety of genes that are involved in the control of the host immune and inflammatory response, and in the regulation of cellular proliferation and survival. The constitutive activation of this pathway is associated with inflammatory and autoimmune diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease, in addition to atherosclerosis, Alzheimer's disease, cancer and diabetes. One of the key steps in activating the NF-kappaB pathway is the stimulation of the IkappaB (inhibitor of kappaB) kinases. Recent data indicate that these kinases activate the NF-kappaB pathway through distinct steps that are operative in both the cytoplasm and the nucleus. A better understanding of the mechanisms that activate this pathway provides the potential for defining new therapeutic targets that might prevent the aberrant activation of NF-kappaB in a variety of human diseases.

Animals↗
PubMed2003

Localization of the iron transport proteins Mobilferrin and DMT-1 in the duodenum: the surprising role of mucin.

There are two pathways for inorganic iron uptake in the intestine, the ferric pathway, mediated by the key protein mobilferrin, and the ferrous pathway, mediated by DMT-1. Previous studies reported that the amount of DMT-1 increased in the intestinal mucosa in iron deficiency and the increase was seen in the apical portion of the villus of the duodenal mucosa. Mobilferrin did not quantitatively increase but became localized at the cell membrane. However, studies on fresh tissue have not previously been performed and the localization to the microvillae has not been demonstrated. In order to more definitively localize these proteins immunofluorescent and electron microscopic studies were undertaken. Samples were also subjected to biochemical analysis and Western analysis. In iron-deficient animals both DMT-1 and Mobilferrin were concentrated in the apical surface of the villae. Electron microscopy revealed that the majority of this increase in the amount of these proteins near the luminal surface was due to increased binding of the proteins to mucin in vesicles near the surface. A significant portion of the iron transport proteins was localized in the goblet cells and outside the cell in the luminal mucin, as demonstrated by immunofluorescence, electron microscopy, and isolation of the mucin by cesium chloride gradient centrifugation and Western analysis. A new model for the transport of metal ions was suggested. The metal transport proteins travel from vesicles inside the cell out to the lumen mucin. This increases the surface area and allows a greater portion of the lumen contents to be exposed to the binding proteins. Once the metal is bound to the externalized protein it is internalized into the cell. This explains many of the unique properties of the iron-binding proteins and suggests that it may be a more general model for the absorption of other nutrients.

Animals↗
PubMed2006

pH is an intracellular effector controlling differentiation of oligodendrocyte precursors in culture via activation of the ERK1/2 pathway.

We reported previously that onset of oligodendrocyte precursor cell (OPC) differentiation is accompanied by an increase in intracellular pH (pH(i)). We show that OPC differentiation is dependent primarily on a permissive pH(i) value. The highest differentiation levels were observed for pH(i) values around 7.15 and inhibition of differentiation was observed at slightly more acidic or alkaline values. Clamping the pH(i) of OPCs at 7.15 caused a transient activation of ERK1/2 that was not observed at more acidic or alkaline values. Furthermore, inhibition of ERK activation with the UO126 compound totally prevented OPC differentiation in response to pH(i) shift. These results indicate that pH(i), acting through the ERK1/2 pathway, is a key determinant for oligodendrocyte differentiation. We also show that this pH(i) pathway is involved in the process of retinoic acid-induced OPC differentiation.

Animals↗
PubMed2000

A novel mutant of the type I restriction-modification enzyme EcoR124I is altered at a key stage of the subunit assembly pathway.

The HsdS subunit of a type I restriction-modification (R-M) system plays an essential role in the activity of both the modification methylase and the restriction endonuclease. This subunit is responsible for DNA binding, but also contains conserved amino acid sequences responsible for protein-protein interactions. The most important protein-protein interactions are those between the HsdS subunit and the HsdM (methylation) subunit that result in assembly of an independent methylase (MTase) of stoichiometry M(2)S(1). Here, we analysed the impact on the restriction and modification activities of the change Trp(212)-->Arg in the distal border of the central conserved region of the EcoR124I HsdS subunit. We demonstrate that this point mutation significantly influences the ability of the mutant HsdS subunit to assemble with the HsdM subunit to produce a functional MTase. As a consequence of this, the mutant MTase has drastically reduced DNA binding, which is restored only when the HsdR (restriction) subunit binds with the MTase. Therefore, HsdR acts as a chaperon allowing not only binding of the enzyme to DNA, but also restoring the methylation activity and, at sufficiently high concentrations in vitro of HsdR, restoring restriction activity.

Catalysis↗
PubMed2006

Lipid and lipoprotein dysregulation in insulin resistant states.

Insulin resistant states are commonly associated with an atherogenic dyslipidemia that contributes to significantly higher risk of atherosclerosis and cardiovascular disease. Indeed, disorders of carbohydrate and lipid metabolism co-exist in the majority of subjects with the "metabolic syndrome" and form the basis for the definition and diagnosis of this complex syndrome. The most fundamental defect in these patients is resistance to cellular actions of insulin, particularly resistance to insulin-stimulated glucose uptake. Insulin insensitivity appears to cause hyperinsulinemia, enhanced hepatic gluconeogenesis and glucose output, reduced suppression of lipolysis in adipose tissue leading to a high free fatty acid flux, and increased hepatic very low density lipoprotein (VLDL) secretion causing hypertriglyceridemia and reduced plasma levels of high density lipoprotein (HDL) cholesterol. Although the link between insulin resistance and dysregulation of lipoprotein metabolism is well established, a significant gap of knowledge exists regarding the underlying cellular and molecular mechanisms. Emerging evidence suggests that insulin resistance and its associated metabolic dyslipidemia result from perturbations in key molecules of the insulin signaling pathway, including overexpression of key phosphatases, downregulation and/or activation of key protein kinase cascades, leading to a state of mixed hepatic insulin resistance and sensitivity. These signaling changes in turn cause an increased expression of sterol regulatory element binding protein (SREBP) 1c, induction of de novo lipogensis and higher activity of microsomal triglyceride transfer protein (MTP), which together with high exogenous free fatty acid (FFA) flux collectively stimulate the hepatic production of apolipoprotein B (apoB)-containing VLDL particles. VLDL overproduction underlies the high triglyceride/low HDL-cholesterol lipid profile commonly observed in insulin resistant subjects.

Animals↗
PubMed2005

Activation of the lectin pathway in murine lupus nephritis.

In systemic lupus erythematosus (SLE), hypocomplementaemia and complement deposition have been described both in man and in experimental models. A major involvement of the classical pathway of complement activation has been demonstrated in this disease, however relatively little is known about the involvement of the lectin pathway. Therefore in the present study we have analyzed the activity of all three pathways of complement activation in murine models of SLE. In the mouse, MBL is expressed in two forms, namely MBL-A and MBL-C. In the present study young and old MRL-lpr and control MRL+/+ mice were compared for the levels of complement activity with specific attention for the lectin pathway. It was found that upon aging of both MRL-lpr and MRL+/+ mice, a marked decrease in the activity of the classical pathway (CP) occurs. Levels of alternative pathway (AP) and lectin pathway (LP) activity remain unchanged. Key-molecules of these pathways, C1q, C3, MBL-A and MBL-C were analyzed and were all found to be decreased in aged mice of both strains. The levels of MBL-A and MBL-C showed a high degree of correlation and decreased equally. In aged MRL-lpr mice in which autoimmunity is most pronounced, we observed high autoantibody titers and strong deposition of glomerular immune complexes in association with deposition of C1q, C3, MBL-A and MBL-C. In conclusion, these data suggest that in addition to the classical pathway and the alternative pathway also the lectin pathway of complement activation is involved in murine lupus nephritis.

Animals↗
PubMed2003

Enzymology of repair of etheno-adducts.

Etheno(epsilon)-adducts such as 1,N(6)-ethenoadenine (epsilon A), 3,N(4)-ethenocytosine (epsilon C), N(2),3-ethenoguanine (N(2),3-epsilon G), and 1,N(2)-ethenoguanine (1,N(2)-epsilon G) are produced in cellular DNA by two independent pathways: (i) by reaction with oxidised metabolites of vinyl chloride, 2-chloroacetaldehyde and 2-chloroethylene oxide; (ii) by endogenous processes through the interaction of lipid peroxidation (LPO)-derived aldehydes and hydroxyalkenals. They have been found in DNA isolated from human and rodent tissues. However, the levels of adducts were significantly increased by cancer risk factors contributing to lipid peroxidation and oxidative stress. The highly mutagenic and genotoxic properties of epsilon-adducts have been established in vitro by analysing steady-state kinetics of primer extension assays and in vivo by site-specific mutagenesis in mammalian cells. Therefore, the repair processes eliminating exocyclic adducts from DNA should play a crucial role in maintaining the stability of genetic information. The epsilon-adducts are eliminated by the base excision repair (BER) pathway, with DNA glycosylases being the key enzymes of this pathway. They remove epsilon-adducts from DNA by hydrolysing the N-glycosidic bond between the damaged base and deoxyribose, leaving an abasic site in DNA. The ethenobase-DNA glycosylases have been identified and their enzymatic properties described. They are specific for a given epsilon-base although they can also excise different types of modified bases, such as alkylated purines, hypoxanthine and uracil. The fact that ethenoadducts are recognised and excised with high efficiency by various DNA glycosylases in vitro suggests that these enzymes may be responsible for repair of these mutagenic lesions in vivo, and thus constitute important contributors to genetic stability.

Adenine↗
PubMed2000

Solution structure of N-TRADD and characterization of the interaction of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.

TRADD is a multifunctional signaling adaptor protein that is recruited to TNFR1 upon ligand binding. The C-terminal of TRADD comprises the "death domain" that is responsible for association of TNFR1 and other death domain-containing proteins such as FADD and RIP. The N-terminal domain (N-TRADD) promotes the recruitment of TRAF2 to TNFR1 by binding to the C-terminal of TRAF2, leading to the activation of JNK/AP1 and NF-kappa B. The solution structure of N-TRADD was determined, revealing a novel protein fold. A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways.

Amino Acid Sequence↗
PubMed1999

Diterpene synthesis in Stevia rebaudiana: recruitment and up-regulation of key enzymes from the gibberellin biosynthetic pathway.

Stevia rebaudiana Bertoni leaves accumulate a mixture of at least eight different glycosides derived from the tetracyclic diterpene steviol. These natural products taste intensely sweet and have similar biosynthetic origins to those of gibberellic acid (GA). The initial steps leading to the formation of GA result from the two-step cyclization of geranylgeranyl diphosphate (GGDP) to (-)-kaurene via the action of two terpene cyclases (-)-copalyl diphosphate synthase (CPS) and (-)-kaurene synthase (KS). Steviol biosynthesis probably uses the same mechanism although the genes and enzymes from S. rebaudiana that are involved in the cyclization of GGDP have not been characterized. We have isolated both the CPS and KS genes from S. rebaudiana and found that recombinant CPS and KS were catalytically active, suggesting that the CPS and KS genes participate in steviol biosynthesis. The genes coding for CPS and KS are usually present in single copies in most plant species and their expression is normally low and limited to rapidly growing tissues. The KS gene has been duplicated in the S. rebaudiana genome and both the KS and CPS genes are highly expressed in mature leaves, a pattern opposite to that found with GA biosynthesis. This pattern may, at least in part, lead to temporal and spatial separation of GA and steviol biosynthesis and probably helps to prevent over-expression from interfering with normal GA metabolism. Our results show that CPS and KS are part of the steviol glycoside biosynthetic pathway and that Stevia rebaudiana has recruited two genes to secondary metabolism from a highly regulated pathway involved in hormone biosynthesis.

Alkyl and Aryl Transferases↗