Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte macrophage colony-stimulating factor (GM-CSF) binds to the high-affinity GM-CSF receptor (GMR) consisting of alpha and beta subunits and induces rapid tyrosine phosphorylation, activation of early response genes, and proliferation of hematopoietic cells. The alpha subunit is the primary cytokine binding component and the beta subunit is required for high-affinity binding as well as for signal transduction. Using tyrosine kinase inhibitors and cytoplasmic deletion mutants of the beta subunit, we obtained evidence that there are at least two distinct pathways downstream of the GMR in BA/F3 cell, one which is essential for proliferation, leads to the c-myc gene activation, and is sensitive to herbimycin and genistein. Activation of this pathway depends on the cytoplasmic region between amino acid positions 455 and 517 of the beta subunit. The second pathway, which leads to activation of c-fos and c-jun genes, is only partially sensitive to herbimycin, is resistant to genistein and depends on the region between amino acid positions 626 and 763 of the beta subunit. Unexpectedly, the c-fos mRNA induction was augmented by genistein. The enhanced expression of c-fos mRNA by genistein also occurred with stimulation with cAMP, PMA, or EGF in NIH3T3 cells. It thus seems likely that genistein affects a common pathway downstream of these signals.
Mol Biol Cell 1993 Oct
PMID:Differential regulation of early response genes and cell proliferation through the human granulocyte macrophage colony-stimulating factor receptor: selective activation of the c-fos promoter by genistein. 829 95

CD28 is a 44 kDa Ig superfamily cell surface molecule expressed on most mature T cells. Through its interaction with the recently identified B7/BB1 counter-receptor, it is believed to play an important role as a co-stimulator of T cells along with the TCR-CD3 complex. Activation of T cells with CD28 mAbs synergizes with TCR-CD3 and CD2 stimulation, resulting in long term T cell proliferation, differentiation of cytotoxic T cells and production of large amounts of cytokines. In order to further delineate the role of CD28 in signal transduction and T cell activation, human CD28 was transfected into CD3+ murine T cell hybridomas. High levels of cell surface CD28 expression was achieved by protoplast fusion. The transfected molecule retained all the native CD28 mAb epitopes found on human T cells. In these transfectants, CD28 mAbs, similarly to CD3 mAbs, were able to induce Ca2+ mobilization, IL-2 promoter induction (measured as beta-galactosidase activity in T cells hybridomas pre-transfected with the IL-2-lac Z reporter gene), IL-2 secretion, TNF alpha production and apoptosis (observed as growth arrest and genome fragmentation). The parental host cells, or cells transfected with vector alone, responded only to mAbs to CD3. IL-2 secretion in the transfectants was obtained using either an IgM mAb to CD28 or IgG mAbs presented on the surface of IgG-FcR+ B lymphoma cells. Optimal activation via CD28 was inhibited by suboptimal concentrations of soluble CD3 mAb, suggesting an interaction between the two pathways. The immunosuppressive drugs Cyclosporin A and FK506 completely blocked CD28 and CD3 mediated IL-2 production in these transfectants whereas rapamycin had only a partial inhibitory effect. Finally, since the transfected human CD28 molecule confers full functional responsiveness to the murine T cell hybridomas without the need for costimulators such as PMA, this model is ideal for studying the structure-function relationships of the CD28 molecule as well as the transmembrane and cytoplasmic associations implied in CD28 signaling.
Mol Immunol 1994 Jan
PMID:Functional expression of human CD28 in murine T cell hybridomas. 830 98

Terminal deoxynucleotidyl Transferase (TdT) play an essential role in the immune system differentiation. KM-3 cells are lymphoblastoid cells expressing the TdT and when induced to differentiate by phorbol ester (PMA) they loose this enzyme. Therefore, because of the suggested involvement of polyphosphoinositide in controlling the nuclear events it has been analyzed the phosphorylation of nuclear polyphosphoinositides during KM-3 differentiation. When the differentiated state is reached the phosphorylation level of PIP2 increases in isolated nuclei and this is accompanied by a concomitant decrease of PIP and PA, hinting at a correlation between polyphosphoinositide metabolism and TdT expression.
Biochem Mol Biol Int 1993 Apr
PMID:Phorbol ester induces changes in the synthesis of nuclear polyphosphoinositides and expression of terminal deoxynucleotidil transferase (TdT) in nuclei of KM-3 cells. 839 17

Staurosporine has been used in several studies to investigate the role of protein kinase C (PKC) in secretory responses of islets of Langerhans to insulin secretagogues. We have assessed the effect of staurosporine on: [i] islet PKC activity in vitro; [ii] the stimulation of insulin secretion by nutrient secretagogues and [iii] the stimulation of protein phosphorylation and insulin secretion in electrically permeabilised islets. All experiments were carried out on rat isolated islets of Langerhans, either intact or permeabilised by high voltage discharge (3.4 kV/cm). The activity of PKC partially purified from rat islets was inhibited by staurosporine (1.6-400 nM) in a concentration-dependent manner. Staurosporine also inhibited insulin secretion stimulated by both glucose and glyceraldehyde, with maximal effects at 50 nM. After prolonged exposure of islets to the tumour-promoting phorbol ester, 4 beta phorbol myristate acetate (4 beta PMA), a procedure which depletes islet PKC activity, staurosporine still inhibited both glucose- and glyceraldehyde-stimulated insulin release. In electrically permeabilised islets, staurosporine inhibited both Ca(2+)- and cyclic AMP-stimulated protein phosphorylation and insulin secretion. These results suggest that staurosporine should not be used as a selective inhibitor of PKC in rat islets.
Mol Cell Endocrinol 1993 Jul
PMID:Staurosporine inhibits protein kinases activated by Ca2+ and cyclic AMP in addition to inhibiting protein kinase C in rat islets of Langerhans. 839 22

The transcription factor NF-kappa B appears to play an important role in immunoglobulin gene expression and lymphokine production, and may play a role in primary B cell activation. Constitutive nuclear expression of NF-kappa B has been found in all mature B cell lines with the notable exception of the murine plasmacytoma, S107. We report herein that S107 cells express cytoplasmic kappa B-binding material detected by electrophoretic mobility shift assay that by several criteria represents authentic NF-kappa B. Despite the presence of cytoplasmic NF-kappa B, several stimuli known to induce nuclear translocation of NF-kappa B failed to do so in S107 cells, including: the PKC agonist, PMA; the protein synthesis inhibitor, cycloheximide; and LPS. Transfection of S107 cells with a kappa B-CAT reporter gene construct confirmed the absence of functional activity. Importantly, a global failure of nuclear transcription factor expression was ruled out by the ability of PMA to induce nuclear expression of another trans-acting factor, AP-1. Thus, rather than lacking NF-kappa B altogether, S107 cells manifest disordered regulation of NF-kappa B in which cytoplasmic material is incapable of translocation to the nucleus. While Northern analysis failed to reveal a gross defect in the mRNA coding for the DNA binding subunit of NF-kappa B, UV-photo-cross-linking followed by denaturing gel electrophoresis demonstrated the presence of a cytoplasmic kappa B-binding protein of abnormally elevated molecular size. This finding suggests that the abnormal regulation of NF-kappa B in S107 cells is associated with the appearance of an unusual kappa B-binding molecule.
Mol Immunol 1993 Apr
PMID:Abnormal kappa B-binding protein in the cytoplasm of a plasmacytoma cell line that lacks nuclear expression of NF-kappa B. 846 29

In human renal mesangial cells, platelet derived growth factor (PDGF)-A chain is subject to regulation by protein kinase C (PKC) activator, phorbol ester (phorbol 12-myristate 13-acetate, PMA). Treatment of mesangial cells with PMA increases PDGF-A chain mRNA abundance as analyzed by Northern blot hybridization. In contrast to the effect of PMA, the inactive analog phorbol had no effect on PDGF-A chain mRNA levels, while the PKC inhibitor H7 markedly reduced the PMA-induced increment in PDGF-A chain mRNA. To determine the mechanism by which PMA increases the abundance of this gene, transcription rate was measured by nuclear transcript elongation assay. Treatment of mesangial cells with PMA resulted in a 2-fold increase in PDGF-A chain gene transcription. In addition, we analyzed the effects of PMA on PDGF-A chain mRNA half-life as measured directly by pulse-chase method. PDGF-A chain mRNA has a half-life of about 106 min. The PDGF-A chain mRNA half-life was reduced by 30% (t1/2 = 74 min) when mesangial cells were incubated with PMA. Our results demonstrate that in human renal mesangial cells, the regulation of PDGF-A chain gene expression by PMA is primarily at the level of transcription.
Mol Cell Endocrinol 1993 Feb
PMID:Platelet derived growth factor-A chain gene expression in cultured mesangial cells: regulation by phorbol ester at the level of mRNA abundance, transcription and mRNA stability. 847 49

Recent studies in several non-primate species have suggested that prostaglandin F2 alpha (PGF2 alpha) inhibits luteal cell progesterone production by activating the calcium and phospholipid-dependent protein kinase, protein kinase C (PKC). This study investigated the presence of PKC in human ovarian cells and assessed the ability of PGF2 alpha and its structural analogue, cloprostenol, to generate inositol polyphosphates and activate PKC. PKC was detected in cultured human granulosa-lutein cells and human luteal cells (from mid-late luteal phase). The major proportion of PKC detected was cytosol-associated in both cell types. Cloprostenol increased the generation of inositol polyphosphates in cultured human granulosa-lutein cells in a dose- and time-dependent manner. In addition both cloprostenol and PGF2 alpha activated PKC (as assessed by redistribution of enzyme activity from a principally cytosol-associated form to a membrane-associated form) in both granulosa-lutein and luteal cells. Short-term exposure of both cell types to phorbol myristate acetate (4 beta-PMA) activated PKC, whilst prolonged exposure of human granulosa-lutein cells to 4 beta-PMA led to a > 85% loss of total PKC activity. The inactive phorbol ester, 4 alpha-PMA, had no effect on PKC activity when exposed to cells for up to 20 h. These results demonstrate the presence of PKC in human ovarian cells and the ability of PGF2 alpha to induce translocation/activation of this kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1993 Feb
PMID:Prostaglandin F2 alpha activates protein kinase C in human ovarian cells. 847 54

A cDNA clone was isolated for a fourth pma gene encoding a putative plasma membrane H(+)-ATPase of Nicotiana plumbaginifolia. The sequence of the predicted 952 residue PMA4 polypeptide was compared with those of other known plant PMAs, revealing a higher identity with the Arabidopsis thaliana proteins (86-89%) than with the other three N. plumbaginifolia PMA proteins (80-82%). This supports the view that there are two pma subfamilies which probably arose from a gene duplication predating the separation of the Dilleniidae and Asteridae plant subclasses. Measured pma4 transcript levels indicate that pma4 is similarly expressed in root, stem, leaf, and flower tissues, contrary to the pmal-3 subfamily whose members displayed differential expression according to the organ.
Plant Mol Biol 1993 Mar
PMID:Identification and characterization of a second plasma membrane H(+)-ATPase gene subfamily in Nicotiana plumbaginifolia. 849 Jan 41

The cell surface expression of the CD32 receptors for the Fc portion of immunoglobulin G (Fc gamma RII-CD32) is regulated by agents such as phorbol esters (PMA) and cytokines. In this study, we investigated the effects of PMA and interferon-gamma (IFN-gamma) on the expression of CD32C mRNA in U937 cells. When U937 (CD32+) cells are incubated with either PMA or IFN-gamma a significant enhancement of CD32C mRNA expression is observed with maximum enhancement at 18 hrs post-PMA and IFN-gamma addition. The addition of actinomycin D (ActD), a transcriptional inhibitor, together with either PMA or IFN-gamma diminishes the enhanced levels of CD32C mRNA to the basal levels, indicating that transcriptional regulation is involved in this modulatory process. The addition of cyclohexamide (CX), a protein synthesis inhibitor, to cultures undergoing stimulation with either PMA or IFN-gamma, increased the levels of CD32C mRNA synthesis suggesting that regulatory degradation proteins may be involved. The PMA and IFN-gamma stimulated CD32C mRNA is degraded within 2 hr post-stimulation and this degradation is delayed by the inhibition of de novo protein synthesis. These results, taken together with our previous studies of CD32A mRNA regulation in U937 cells stimulated with PMA, indicate that both the CD32A and C isomer mRNAs are rapidly degraded; however, CD32A and C isomer mRNAs are differentially regulated. At the optimal PMA dose, the time of mRNA stimulation of CD32A and C mRNA varies and the addition of CX to U937 cells together with PMA enhanced the levels of CD32C mRNA but had no effect on CD32A mRNA levels. These results imply that the differential regulation of the two CD32 isomers may result in differential function.
Mol Immunol 1993 Jun
PMID:CD32C (Fc gamma RIIC) mRNA expression and regulation. 850 44

We report the genomic structure and chromosomal localization of the human zinc-finger gene pAT133. This gene belongs to a family of four human immediate-early genes (pAT133, pAT225/EGR1, pAT591/EGR2 and EGR3), which have almost identical zinc-finger domains, but distinct flanking regions. The human pAT133 gene is organized in two exons, and has been mapped to human chromosome 2p13. We determined the transcription start site by primer extension analysis and identified several regulatory elements in the upstream regulatory sequence. The pAT133-promoter functions as an inducible promoter in human T cells and in fibroblasts, as constructs containing the bacterial chloramphenicol acetyl transferase (CAT) gene driven by a 943 bp pAT133-promoter fragment were induced in these cells by stimulation with PHA/PMA or by serum, respectively. The serum inducible pAT133-promoter lacks consensus serum response elements. However, we could demonstrate that two CArG-like motifs with a single base exchange confer serum inducibility to a reporter construct. Due to their serum responsiveness, these elements may serve as a high affinity binding sites for the recently described human serum response factor-related proteins.
Hum Mol Genet 1993 Apr
PMID:Genomic organization, chromosomal localization and promoter function of the human zinc-finger gene pAT133. 850 97


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