Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
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PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

It is well established that prolactin (PRL) sustains, while prostaglandin F(2 alpha) (PGF(2 alpha)) curtails, progesterone production by the rat corpus luteum (CL). We have previously shown that the actions of both molecules converge on the 20 alpha-HSD gene and control its expression in a dramatically opposed manner. In this investigation, we have found twelve more genes that are inversely regulated by PRL and PGF(2 alpha). In addition to 20 alpha-HSD, PGF(2 alpha) stimulated and PRL inhibited PGF(2 alpha)-receptor, phospholipase C delta(1) and TGF beta(1) expression. In contrast PRL stimulated and PGF(2 alpha) inhibited the LH receptor, 11 beta-HSD2, sterol carrier protein 2, mitochondrial glutathione S-transferase (GST), GST mu(2), inhibitory DNA-binding proteins 1, 2, and 3, and calcium binding protein 2. We have also identified new target genes for PRL and PGF(2 alpha). PGF(2 alpha) stimulated the expression of genes involved in cell signaling such as cell adhesion kinase-beta, ERK3, FRA2, IL-2 receptor, and 14-3-3 proteins. PGF(2 alpha) also up-regulated the expression of the sodium channel beta(1), Na/K ATPase, annexin IV, GST7pi, and P450 reductase. In contrast PGF(2 alpha) inhibited the expression of two genes involved in cell cycle: cyclin D2 and retinoblastoma related protein (Rb2/p130). It also inhibited genes involved in estradiol (P-450(AROM)) and cholesterol biosynthesis (HMG-CoA synthase), as well as genes involved in tissue remodeling: VEGF and TIMP3. PRL had a profound inhibitory effect on the expression of genes encoding the ADP-ribosylation factor 3, annexin V and c-jun, yet increased the expression of P450scc, 3beta-HSD, and SR-B1 (HDL-receptor), all genes involved in steroidogenesis. PRL also stimulated the expression of beta(2)-microglobulin, TIMP2, cytochrome c oxidase IV, cathepsin H and L, and copper-zinc superoxide dismutase as well as elongation factor SIII, heat shock protein-60 and mitochondrial ATP synthase-D. In conclusion, this investigation has revealed a "yin-yang" relationship between PRL and PGF(2 alpha) in regulating certain critical genes in the rodent CL, and has demonstrated novel regulation by these factors of other important genes involved in luteal function.
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PMID:Opposite effect of prolactin and prostaglandin F(2 alpha) on the expression of luteal genes as revealed by rat cDNA expression array. 1151 96

Decidual transformation of human endometrial stromal (ES) cells requires sustained activation of the protein kinase A (PKA) pathway. In a search for novel transcriptional mediators of this process, we used differential display PCR analysis of undifferentiated primary ES cells and cells stimulated with 8-bromo-cAMP (8-Br-cAMP). We now report on the role of forkhead homologue in rhabdomyosarcoma (FKHR), a recently described member of the forkhead/winged-helix transcription factor family, as a mediator of endometrial differentiation. Sustained 8-Br-cAMP stimulation resulted in the induction and nuclear accumulation of FKHR in differentiating ES cells. Immunohistochemical studies revealed that endometrial stromal expression of FKHR in vivo is confined to decidualizing cells during the late secretory phase of the cycle and coincides with the expression of CCAAT/enhancer-binding protein beta (C/EBPbeta). Reporter gene studies showed that FKHR potently enhances PKA-dependent activation of the tissue-specific decidual prolactin (dPRL) promoter, a major differentiation marker in human ES cells. Transcriptional augmentation by FKHR was effected through functional cooperation with C/EBPbeta and binding to a composite FKHR-C/EBPbeta response unit in the proximal promoter region. Furthermore, FKHR and C/EBPbeta were shown to interact directly in a glutathione S-transferase pull-down assay. These results provide the first evidence of regulated expression of FKHR and demonstrate that FKHR has an integral role in PKA-dependent endometrial differentiation through its ability to bind and functionally cooperate with C/EBPbeta.
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PMID:Cyclic AMP-induced forkhead transcription factor, FKHR, cooperates with CCAAT/enhancer-binding protein beta in differentiating human endometrial stromal cells. 1189 44

To prepare reagents for a study of the interactions of prolactin (PRL) and growth hormone (GH) receptors (Rs) with suppressor of cytokine signaling (SOCS) proteins in living cells by fluorescence resonance energy transfer methodology, the respective proteins were tagged with cyan (CFP) or yellow (YFP) fluorescent protein. Constructs encoding ovine (o)PRLR-YFP, oPRLR-CFP, oGHR-YFP, and oGHR-CFP tagged downstream of the receptor DNA were prepared in the plasmid pcDNA plasmid and tested for biological activity in HEK 293T cells transiently cotransfected with those constructs and the reporter gene encoding luciferase. All four constructs were biologically active and as potent as their untagged counterparts. Cells transfected with those proteins exhibited fluorescence in the cytoplasm and the membrane. Constructs encoding DNA tagged with YFP or CFP upstream of SOCS1, SOCS2, SOCS3, and SOCS6 were prepared in pECFP-C1 and pEYFP-C1 plasmids. The biological activities of SOCS1 and SOCS3 tagged at their amino termini were assayed by their ability to inhibit placental lactogen (PL)- or GH-induced activation of JAK2/STAT5-mediated luciferase transcription in HEK 293T cells; the activity of SOCS2 was assayed by its ability to abolish SOCS1-induced inhibition. The tagged proteins exhibited biological activity that was equal to or even more potent than their untagged counterparts. The biological activities of CFP-SOCS2 and YFP-SOCS2 were also assayed using GST-GHR binding assay. Their interaction with the cytosolic domain of GHR was equivalent to their respective untagged counterparts. The biological activity of the construct encoding SOCS6 was not tested because of lack of a suitable assay. Cells transfected with eight of these tagged constructs expressed the fluorescent proteins in both the nucleus and cytosol; the tagged SOCS2 was localized mostly in the latter compartment.
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PMID:Preparation and expression of biologically active prolactin and growth hormone receptors and suppressor of cytokine signaling proteins 1, 2, 3, and 6 tagged with cyan and yellow fluorescent proteins. 1218 26

This study concerned the minimum and optimum effective doses of calcium chloride needed for induction of chemosterilization in male albino rats, 30 days after a single intratesticular injection of calcium chloride (CaCl2.2H2O) solution at 2.5, 5, 10 or 20 mg per 100 g body weight per testis. There was a significant diminution in the relative wet weight of the sex organs (p<0.01), epididymal sperm count (p<0.001), plasma concentration of testosterone (p<0.01), testicular activities of delta5,3beta-hydroxy steroid dehydrogenase (delta5,3beta-HSD), 17beta-hydroxy steroid dehydrogenase (17beta-HSD) (p<0.01), glutathione S-transferase (GST) (p<0.01), superoxide dismutase (SOD) (p<0.01), and peroxidase (p<0.01), significant elevations in testicular content of malondialdehyde (MDA) and conjugated dienes (p<0.01), along with derangement of seminiferous tubular architecture and degeneration of the Leydig cells in the testis and elevations in the concentrations in the plasma of LH and FSH (p<0.01), commencing at a dose of 5 mg, with the greatest effects at a dose of 20 mg. No significant alterations in these factors occurred at the dose of 2.5 mg in comparison to the control that received only the vehicle. There was no significant alteration in the plasma concentrations of prolactin (p>0.05), corticosterone (p>0.05) or fasting blood glucose or in the rectal temperature (p>0.05) at any of the doses relative to the control group, suggesting that this chemosterilizing procedure did not exert any chronic stress on the experimental animals. From these observations, it may be suggested that 5 mg should be considered as the minimum dose, and 10 mg or 20 mg as the optimum dose, whereas 2.5 mg was ineffective for induction of chemosterilization. There would seem to be little point in using more than 20 mg of calcium chloride for this purpose. Intratesticular injection of calcium chloride at an effective dose may be considered as an alternative to surgical castration.
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PMID:Dose-dependent response to an intratesticular injection of calcium chloride for induction of chemosterilization in adult albino rats. 1250 39

The prolactin receptor (PrlR) is a member of the cytokine receptor superfamily that lacks an intrinsic kinase domain and relies on the cytoplasmic Jak tyrosine kinases to transduce signals. Prolactin-induced Jak2 activation and consequent tyrosine phosphorylation of the receptor and downstream signaling molecules have been studied, but phosphorylation of the PrlR on serine or threonine residues has not been reported. Here we describe a novel interaction between the PrlR and the phosphoserine/phosphothreonine-binding 14-3-3 proteins. This association is mediated by the KCST391WP motif, which occurs in the major functional isoform of the human receptor and is conserved among a wide variety of species. Mutagenesis of threonine 391 to alanine significantly impaired 14-3-3 binding to the PrlR in both glutathione S-transferase pulldown and coimmunoprecipitation assays. In breast carcinoma and mouse mammary epithelial cell lines, the endogenous receptor was found to associate with glutathione S-transferase-14-3-3 proteins independent of prolactin stimulation. A phospho-specific peptide antibody was generated and used to demonstrate phosphorylation of Thr391 in vivo. Phosphorylation of this site was found to be sensitive to okadaic acid, a specific inhibitor of serine/threonine protein phosphatases. Interestingly, the T391A PrlR mutant exhibited increased basal and prolactin-induced tyrosine phosphorylation compared with the wild-type receptor. This was accompanied by a ligand-induced increase in protein kinase B and Erk activation but not that of Stat5a. Phosphorylation of the receptor on Thr391 may therefore provide a new mechanism by which prolactin signaling is attenuated.
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PMID:Threonine 391 phosphorylation of the human prolactin receptor mediates a novel interaction with 14-3-3 proteins. 1281 9

Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.
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PMID:Understanding breast cancer risk -- where do we stand in 2005? 1578 78

Interferon regulatory factor-1 (IRF-1) is a positive transcription factor for genes involved in immune response, cell growth regulation and apoptosis in mammalian cells. Many agents like virus, interferon (IFN), double-stranded RNA (dsRNA), proinflammatory cytokines, prolactin etc. induce IRF-1 at transcriptional level. IRF-1 transcriptionally activates many IRF-1-regulated genes during normal physiological and pathological conditions. We have expressed recombinant mouse IRF-1 (329 amino acids) as a GST(glutathione-S-transferase)-IRF-1 fusion protein from a 1029 bp IRF-1 cDNA in pGEX-2TK expression vector in Escherichia coli XL-1 blue cells. Recombinant GST-IRF-1 was highly expressed as a approximately 66 kDa soluble protein by IPTG-induction, and was biologically active in terms of its DNA binding activity with a 24 bp specific oligonucleotide, i.e. 32P(GAAAGT)4 but not with a similar but nonspecific oligonucleotide i.e. 32P(GAAA)6. GST-alone expressed from the vector did not bind 32P(GAAAGT)4. We observed multiple (1-4) GST-IRF-1-(GAAAGT)4 protein-DNA complexes which were competed out by 25x- to 100x-fold molar excess of (GAAAGT)4 showing that the complexes 1-4 were specific for IRF-1. Such GAAANN (N = any nucleotide) hexanucleotides occur in the promoters of many virus- and interferon-inducible mammalian genes. Multimeric GAAAGT/C sequences are inducible by virus, IFN, dsRNA and IRF-1. Specificity of DNA binding by IRF-1 lies in the 5th and 6th nucleotides in the GAAAGT sequence. Multiple IRF-1-DNA complexes should stimulate transcription by IRF-1.
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PMID:Expression and DNA binding activity of the recombinant interferon regulatory factor-1 (IRF-1) of mouse. 1602 83

cDNA encoding pituitary (PRL) of giant panda was obtained using RT-PCR and expressed in E. coli. The results revealed that panda PRL cDNA encodes a precursor protein of 229 amino acids including a putative signal peptide of 30 amino acids and a mature protein of 199 residues with one potential N-glycosylation site. Sequence comparison indicated that panda PRL shares a high degree of identity to other known PRL sequences ranging from 98% with mink PRL to about 50% with rodent PRL. Six cysteine residues and 29 conserved residues distributed in four domains (PD1, PD2, PD3, and PD4) of PRL were observed. through multiple sequence alignment. Fourteen key residues of binding sites 1 and 2 involved in receptor binding are conserved in panda PRL. GST fused recombinant panda PRL protein was efficiently expressed with the form of insoluble inclusion bodies in E. coli BL21 transformed with a pGEX-4T-1 expression vector containing the DNA sequence encoding mature panda PRL. Western blot analysis indicated that GST-panda PRL recombinant protein could be recognized by antibody against human PRL. Our results would contribute to further elucidating the structural and functional characteristics of pituitary PRL and provide a basis for the production of recombinant panda prolactin for future use in the breeding of giant panda.
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PMID:Molecular cloning of giant panda pituitary prolactin cDNA and its expression in Escherichia coli. 1633 6

Macroprolactinemia, in which serum prolactin (PRL) mainly consists of PRL with a molecular mass greater than 100 kDa, has been demonstrated to be associated with hyperprolactinemia. We previously reported that anti-PRL autoantibody is the major cause of macroprolactinemia. In this study, the autoantibody-binding sites (epitopes) on the PRL molecule were examined using deletion mutant PRL. The sera from 159 patients with hyperprolactinemia were screened for macroprolactinemia using the polyethylene glycol method and 18 patients (11%) were diagnosed with macroprolactinemia. The sera from these patients were incubated with glutathione S-transferase-human prolactin (hPRL) fragment fusion proteins immobilized on glutathione sepharose and the amounts of bound immunoglobulin G (IgG) were measured using ELISA. IgG was bound to full-length hPRL1-199 in significantly greater amounts in sera from 14 of 18 patients with macroprolactinemia than in controls. hPRL, but not PRL of other species such as bovine, porcine, rat, or human GH, dose-dependently displaced the binding, suggesting that these patients had hPRL-specific autoantibodies. Deletion of 34 amino acid residues from N-and/or C-terminals significantly reduced the binding and N- or C-terminal fragment alone showed partial but significant binding, suggesting that the major epitopes recognized by anti-PRL autoantibodies are located in both N- and C-terminal residues of the PRL molecule.
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PMID:Anti-prolactin (PRL) autoantibody-binding sites (epitopes) on PRL molecule in macroprolactinemia. 1689 62


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