Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfate conjugation of DHEA and other steroids. From 20 to 25% of subjects are included in a subgroup with high levels of hepatic DHEA ST activity, raising the possibility that this enzyme activity might be controlled by a genetic polymorphism. To understand the molecular mechanisms involved in regulating levels of DHEA ST activity in human tissue, we cloned the human DHEA ST gene, STD. STD spans at least 17 kb and is composed of 6 exons and 5 introns. The locations of the splice junctions for several of the introns are identical to those present in the rat phenol or aryl ST gene, the only other cytosolic ST gene for which the entire exon/intron structure has been reported, as well as those present in two partially characterized genes for the rat senescence marker protein, genes that are also thought to encode ST enzymes. The 5'-flanking region of the human STD gene does not contain canonical TATA or CCAAT elements, but this region is capable of promoting transcription of a reporter gene in Hep G2 cells. Molecular cloning and structural characterization of the human STD gene will make it possible to study genetic mechanisms involved in the regulation of DHEA ST activity in human tissue.
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PMID:Human dehydroepiandrosterone sulfotransferase gene: molecular cloning and structural characterization. 771 Jun 89

Dehydroepiandrosterone (DHEA) sulfotransferase (ST) catalyzes the sulfate conjugation of DHEA and other steroid compounds. The human gene for DHEA ST (STD) was mapped by the polymerase chain reaction to chromosome 19 using human x rodent somatic cell hybrid panels. Fluorescence in situ hybridization was then used to localize the STD gene to the region 19q13.3.
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PMID:Dehydroepiandrosterone sulfotransferase gene (STD): localization to human chromosome band 19q13.3. 773 87

Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) serve important roles in perinatal visual and neural development. A neonatal pig model was used to determine if dietary supplementation with DHA and AA at slightly greater concentrations than normally found in human milk would influence fatty acid accretion in retina. One-day-old piglets were assigned to one of four diets (n = 5/group): (i) STD, standard diet containing fat similar to infant formula; (ii) STD + DHA, 0.7% of fatty acids as DHA; (iii) STD + AA, 0.9% as AA; and (iv) STD + BOTH, 0.8% as DHA plus 1.0% as AA. After 25 d, fatty acids in retina phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were determined. Supplementation with DHA resulted in approximately twofold increases (P < 0.05) in PC-DHA (4.88% in STD vs. 10.03% in STD + DHA and 9.47% in STD + BOTH). Similarly, AA supplementation increased PC-AA 1.3-1.4-fold (4.47% in STD vs. 6.19% in STD + AA and 5.70% in STD + BOTH). For PE, supplementation with either fatty acid or in combination resulted in no significant increases, except for a 1.2-fold increase in DHA for STD + BOTH (32.66%) vs. STD (28.38%). Thus, PC responded to dietary supplementation, with addition of DHA, AA, or BOTH, resulting in increases in respective fatty acids; PE was less responsive, with only STD + BOTH resulting in increased DHA. No significant competition between DHA and AA in incorporation into phospholipids was observed. In conclusion, consumption of a combination of DHA and AA by neonatal pigs supported accretion of DHA in retina phospholipids, while simultaneously supplying the AA necessary for membrane phospholipids and eicosanoid biosynthesis.
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PMID:Retinal fatty acids of piglets fed docosahexaenoic and arachidonic acids from microbial sources. 864 34

Dehydroepiandrosterone sulfotransferase (DHEA ST) catalyzes the sulfation of DHEA and other hydroxysteroids. DHEA ST enzymatic activity in individual human liver biopsy samples has been shown to vary over a five-fold range, and frequency distribution histograms are bimodal, with approximately 25% of subjects included in a high activity subgroup. We set out to characterize the molecular basis for variation in human liver DHEA ST activity. The first step involved performing quantitative Western analysis of cytosol preparations from 92 human liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. There was a highly significant correlation (r(s) = 0.635, P < 0.0001) between levels of DHEA ST activity and immunoreactive protein. We next attempted to determine whether the expression of DHEA ST might be controlled, in part, by a genetic polymorphism. DNA was isolated from three "low" and three "high" DHEA ST activity liver samples. Exons and the 5'-flanking region of the DHEA ST gene (STD) were amplified for each of these samples with the polymerase chain reaction (PCR). When compared with "wild type" STD sequence, some of the samples contained a T --> C transition at DHEA ST cDNA nucleotide 170, located within exon 2, resulting in a Met 57 --> Thr change in amino acid. Other samples contained an A --> T transversion at nucleotide 557 within STD exon 4 that resulted in a Glu 186 --> Val change. STD exons 2 and 4 were then sequenced for DNA isolated from an additional 87 liver samples that had been phenotyped with regard to level of DHEA ST enzymatic activity. The allele frequency for the exon 2 polymorphism in these samples was 0.027, whereas that for the exon 4 polymorphism was 0.038, but neither polymorphism was systematically related to the level of enzyme activity in these samples. Transient expression in COS-1 cells of cDNA that contained the nucleotide 170 and 557 polymorphisms, either separately or together, resulted in decreased expression of both DHEA ST enzymatic activity and level of immunoreactive protein, but only when the nucleotide 557 variant was present. Identification of common genetic polymorphisms within STD will now make it possible to test the hypothesis that those polymorphisms might alter in vivo expression and/or function of this important human steroid-metabolizing enzyme.
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PMID:Human dehydroepiandrosterone sulfotransferase pharmacogenetics: quantitative Western analysis and gene sequence polymorphisms. 901 Mar 52

We have cloned and characterized cDNAs that encode two human hydroxysteroid sulfotransferase (SULT) enzymes, SULT2B1a and SULT2B1b, as well as the single gene that encodes both of these enzymes. The two cDNAs differed at their 5'-termini and had 1050- and 1095-bp open reading frames that encoded 350 and 365 amino acids, respectively. The amino acid sequences encoded by these cDNAs included "signature sequences" that are conserved in all known cytosolic SULTs. Both cDNAs appeared, on the basis of amino acid sequence analysis, to be members of the hydroxysteroid SULT "family, " SULT2, but they were only 48% identical in amino acid sequence with the single known member of that family in humans, SULT2A1 (also referred to as DHEA ST). Northern blot analysis demonstrated the presence of SULT2B1 mRNA species approximately 1.4 kb in length in human placenta, prostate, and trachea and-faintly-in small intestine and lung. Expression of the two human SULT2B1 cDNAs in COS-1 cells showed that both of the encoded proteins catalyzed sulfation of the prototypic hydroxysteroid SULT substrate, dehydroepiandrosterone, but both failed to catalyze the sulfate conjugation of 4-nitrophenol or 17beta-estradiol, prototypic substrates for the phenol and estrogen SULT subfamilies. Both of these cDNAs were encoded by a single gene, SULT2B1. The locations of most exon-intron splice junctions in SULT2B1 were identical to those of the only other known human hydroxysteroid SULT gene SULT2A1 (previously STD). The divergence in 5'-terminal sequences of the two SULT2B1 cDNAs resulted from alternative transcription initiation prior to different 5' exons, combined with alternative splicing. SULT2B1 mapped to human chromosome band 19q13.3, approximately 500 kb telomeric to the location of SULT2A1.
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PMID:Human hydroxysteroid sulfotransferase SULT2B1: two enzymes encoded by a single chromosome 19 gene. 979 94

Cytosolic sulfotransferases (ST) catalyze the sulfation of various phenolic agents, catecholamines, thyroid hormones, steroids, drugs, and procarcinogens, usually resulting in the inactivation and subsequent excretion of the compound. My laboratory's efforts have focused on the cloning of the human phenol-sulfating (PST) members of this gene superfamily, implicated in the bioactivation of the hair growth stimulant, minoxidil. At least two major forms of human PST enzymes have been characterized biochemically, the phenol-preferring PST (P-PST), and the catecholamine-preferring PST (M-PST). Various cDNAs have been cloned representing alleles of 3 gene loci termed as STP1, STP2, and STM, which were all mapped precisely to a small region on human chromosome 16p and to the homologous region of mouse chromosome 7. Human cosmid genomic clones have been sequenced to determine the genomic organization for each of the 3 highly-related genes. All contain 7 coding exons, with conserved intron-exon boundaries, and presumptive alternative tissue-specific promoters. At least one of the 3 PST-encoding genes is responsible for forming minoxidil sulfate in the lower outer root sheath of anagen hair follicles. The steroid sulfating genes, STD and STE, have been cloned by other laboratories. The isozyme products of these genes sulfate DHEA and estrogens, respectively. I hypothesize that either STE or STD is involved in the formation of cholesterol sulfate (CS) in epidermal keratinocytes. CS has been demonstrated by other groups to be an activator of keratinocyte Protein Kinase Ceta, which subsequently results in the activation of epidermal transglutaminase and formation of the cornified envelop. STE or STD might also be involved in bioinactivation of estrogens and androgens within skin. Our recent unpublished results have focused on elucidating the patterns of ST gene expression in cultured keratinocytes and fibroblasts derived from human skin using RT-PCR, to understand which of the 5 different ST genes in involved in the regulation of keratinocyte differentiation and minoxidil-induced hair growth.
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PMID:Molecular biology of the human cytosolic sulfotransferase gene superfamily implicated in the bioactivation of minoxidil and cholesterol in skin. 1043 54

This study was designed to compare the effects of dietary arachidonic acid (AA) versus prostaglandin E(2) (PGE(2)) on bone cell metabolism and bone mass. Twenty-eight piglets from 7 litters were randomized to 1 of 4 treatments for 15 days: fatty acid supplemented formula (FA: 0.8% of total fatty acids as AA and 0.1% of total fatty acids as DHA)+PGE(2) injections (0.1mg/kg/day), FA+saline injections, standard formula (STD: n-6:n-3 of 8:1) + PGE(2) injections or STD+saline injections. PGE(2) resulted in elevated osteoblast activity as indicated by plasma osteocalcin and also reduced urinary calcium excretion. Dietary FA resulted in reduced bone resorption as indicated by urinary N-telopeptide and reduced bone PGE(2). Both PGE(2) and FA treatments independently lead to elevated femur mineral content, but the combined treatment caused a reduction. Thus the mechanisms by which PGE(2) and FA lead to enhanced bone mass are distinct.
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PMID:Dietary arachidonic acid suppresses bone turnover in contrast to low dosage exogenous prostaglandin E(2) that elevates bone formation in the piglet. 1279 61

Recent studies have shown that polyunsaturated fatty acids (PUFA) regulated the functions of membrane receptors in T cells and suppressed T cell -mediated immune responses. But the molecular mechanisms of immune regulation are not yet elucidated. Lipid rafts are plasma membrane microdomains, in which many receptors localized. The purpose of this study was to investigate the effect of DHA on IL-2R signaling pathway in lipid rafts. We isolated lipid rafts by discontinuous sucrose density gradient ultracentrifugation, and found that DHA could change the composition of lipid rafts and alter the distribution of key molecules of IL-2R signaling pathway, which transferred from lipid rafts to detergent-soluble membrane fractions. These results revealed that DHA treatment increased the proportion of polyunsaturated fatty acids especially n-3 polyunsaturated fatty acids in lipid rafts and changed the lipid environment of membrane microdomains in T cells. Compared with controls, DHA changed the localization of IL-2R, STAT5a and STAT5b in lipid rafts and suppressed the expression of JAK1, JAK3 and tyrosine phosphotyrosine in soluble membrane fractions. Summarily, this study concluded the effects of DHA on IL-2R signaling pathway in lipid rafts and explained the regulation of PUFAs in T cell-mediated immune responses.
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PMID:Effect of docosahexaenoic acid on interleukin-2 receptor signaling pathway in lipid rafts. 1741 Jun 76

Docosahexaenoic (DHA; C22:6 n-3), eicosapentaenoic (EPA; C20:5 n-3), palmitic (PA; C16:0), and stearic (SA; C18:0) acids decrease lymphocyte proliferation in concentrations of >50 muM, as observed in our previous study. However, oleic acid (OA; C18:1 n-9) and linoleic acid (LA; C18:2 n-6) increase lymphocyte proliferation at 25 muM. In this study, the effect of these FAs on the interleukin-2 (IL-2) signaling pathway in human lymphocytes was investigated. Cells were isolated from heparinized venous blood of healthy human donors by density-gradient sedimentation. Cells were stimulated with 5 mug/ml concanavalin A and treated with FAs in the absence or presence of IL-2 for 1 hour. CD25-alpha externalization was analyzed by flow cytometry, and Janus kinase 1 (JAK1), JAK3, signal transducer and activator of transcription (STAT) 5, extracellular signal-regulated kinases (ERKs) 1 and 2, Akt, and protein kinase C (PKC)-zeta phosphorylation were analyzed by Western blotting. The expression of CD25-alpha at the cell surface was increased by DHA, SA, and PA but was unaffected by EPA, OA, and LA. PA, SA, DHA, and EPA decreased JAK1, JAK3, STAT5, and Akt phosphorylation induced by IL-2, but OA and LA did not cause any effect. OA and LA increased ERK1/2 phosphorylation, whereas the other FAs caused a marked decrease. PKC-zeta phosphorylation was decreased by OA and LA and was not altered by the remaining FAs. In conclusion, the inhibitory effect of PA, SA, DHA, and EPA on lymphocyte proliferation observed in our previous study was attributable to a decrease in JAK/STAT, ERK, and Akt pathways activated by IL-2. Probably, OA and LA stimulated lymphocyte proliferation by increasing ERK1/2 phosphorylation through PKC-zeta activation. The inhibition of JAK1, JAK3, STAT5, ERK1/2, and Akt phosphorylation caused by DHA, SA, and PA is associated with an alteration of CD25 expression at the cell surface.
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PMID:Regulation of interleukin-2 signaling by fatty acids in human lymphocytes. 2340 92

Neuronal cell death caused by pathophysiological over-activation of glutamate receptors and the subsequent CaII overloading, has been implicated in neurodegeneration after stroke, cerebral trauma and epileptic seizures. Recent findings suggest that certain progesterone metabolites (neurosteroids) such as allopregnanolone and dehydroepiandrosterone can protect neuronal cells from such insults. In the present study, murine P19 cells were induced to differentiate into postmitotic neurons expressing specific neuronal markers, including GABA(A) and NMDA receptors. Activation of NMDA receptors in P19-N neurons resulted in excitotoxic cell death, which involved suppression of the phosphorylation of the survival kinase PKB/Akt. Allopregnanolone and DHEA induced a rapid and prolonged phosphorylation of the Akt kinase and they were able to reverse the NMDA-induced suppression of the PI3-K/Akt pathway. The specificity of the neuroprotective effects of these neurosteroids was confirmed by the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin, as well as by the GABA(A) receptor antagonist, bicuculline. The neurotoxic effect of NMDA on P19-N neurons was directly correlated with increased CaII entry, since the addition of EGTA or BAPTA-AM, significantly suppressed the NMDA-induced decrease of phospho-Akt and subsequent neuronal death. These results suggest that neurosteroids are able to act as survival factors on P19-N neurons, promoting the activation of the PI3-K/Akt pathway through a calcium-entry dependent mechanism.
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PMID:Induction of Akt by endogenous neurosteroids and calcium sequestration in P19 derived neurons. 1852


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