Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cellular response to ionizing radiation includes growth arrest and DNA repair followed by proliferation. Induction of immediate early response genes may participate in signal transduction preceding these phenotypic responses. We analyzed mRNA expression for different classes of immediate early genes (JUN, EGR1, and FOS) after cellular x-irradiation. Increased expression of the EGR1 and JUN genes was observed within 0.5-3 hr following x-ray exposure. Preincubation with cycloheximide was associated with superinduction of JUN and EGR1 in x-irradiated cells. Inhibition of protein kinase C activity by prolonged stimulation with phorbol 12-myristate 13-acetate or the protein kinase inhibitor H7 prior to irradiation attenuated the increase in EGR1 and JUN transcripts. FOS expression was not coregulated with that of EGR1 following x-irradiation, suggesting a distinct regulatory pathway of this gene as compared with its regulation following serum and phorbol ester. These data implicate the EGR1 and JUN proteins as signal transducers during the cellular response to radiation injury and suggest that this effect is mediated in part by a protein kinase C-dependent pathway.
 ...
PMID:Protein kinase C mediates x-ray inducibility of nuclear signal transducers EGR1 and JUN. 190 Sep 38

Intracellular pathways that rapidly stimulate the expression of a mitogen-inducible, zinc-finger encoding gene, EGR1 (Sukhatme et al., Cell 53:37-43), have been characterized in two human fibroblasts strains (WI-38 and HSWP). Serum and epidermal growth factor (EGF) were each found to strongly stimulate EGR1 expression in both cell types. Comparably high levels of expression could also be induced by treatment with the phorbol ester TPA. In cells rendered deficient in PK-C, serum and EGF were each still capable of inducing high levels of EGR1 mRNA, demonstrating that additional non-protein kinase C pathways are capable of stimulating EGR1 expression. In both fibroblasts strains, stimulation of EGR1 expression by all these agents exhibited rapid, transient kinetics and could be superinduced if protein synthesis was inhibited through the addition of cycloheximide. Finally, various agents, known to stimulate/inhibit the activation of another early mitogenic response, the activation of Na/H exchange, were analyzed for their effect on EGR1 expression. Interestingly bradykinin, vasopressin, and Ca ionophores, which dramatically stimulate Na/H exchange, were only weak stimulants of EGR1 expression. Conversely, EGF, which stimulates Na/H exchange poorly, strongly activated EGR1 expression. Hence while EGR1 expression could be triggered by multiple intracellular pathways, its expression does not appear to require the prior activation of Na/H exchange.
 ...
PMID:Multiple intracellular pathways induce expression of a zinc-finger encoding gene (EGR1): relationship to activation of the Na/H exchanger. 254 Nov 39

G0S8 is a member of a set of putative G0/G1 switch regulatory genes (G0S genes) selected by screening cDNA libraries prepared from blood mononuclear cells cultured for 2 hr with lectin and cycloheximide. Comparison of a full-length cDNA sequence with the corresponding genomic sequence reveals an open reading frame of 211 amino acids, distributed across 5 exons. The 24-kD protein has a basic domain preceding a potential helix-loop-helix domain which contains a QTK motif found about 60 amino acids from the carboxyl terminus in the loop region of several helix-loop-helix proteins. There are potential phosphorylation sites for protein kinase C, creatine kinase II, and protein tyrosine kinases and regions of sequence similarity to helix-loop-helix proteins, tyrosine phosphatases, and RNA and DNA polymerases. The genomic sequence contains a CpG island, suggesting expression in the germ line. Potential binding sites for transcription factors are present in the 5' flank and introns; these include Zif268/NGFI-A/EGR1/G0S30, NGFI-B, Ap1, and factors that react with retroviral long terminal repeats (LTRs). There are several potential interferon response elements and a serum response element in the 3' flank overlapping a region of similarity to a cytomegalovirus immediate-early gene enhancer. Many of these motifs are found in immediate-early G0/G1 switch genes; however, we were unable to demonstrate an increase in G0S8 mRNA in response to lectin alone. Sequence similarities are noted between G0S8 and a variety of genes involved in the immune system, in the regulation of retroviruses, and in the cell cycle.
 ...
PMID:A human gene encoding a putative basic helix-loop-helix phosphoprotein whose mRNA increases rapidly in cycloheximide-treated blood mononuclear cells. 817 20

Phosphorylation is one of the major post-translational mechanisms by which the activity of transcription factors is regulated. We have investigated the role of phosphorylation in the regulation of nucleic acid binding activity and the nuclear translocation of WT1. Two recombinant WT1 proteins containing the DNA binding domain with or without a three amino acid (KTS) insertion (WT1ZF + KTS and WT1ZF - KTS) were strongly phosphorylated by protein kinase A (PKA) and protein kinase C (PKC) in vitro. Both PKA and PKC phosphorylation inhibited the ability of WT1ZF + KTS or WT1ZF - KTS to bind to a sequence derived from the WT1 promoter region in gel mobility shift assays. The binding of WT1ZF - KTS to an EGR1 consensus binding site was also inhibited by prior PKA and PKC phosphorylation. We also demonstrate the RNA binding activity of WT1, but this was not altered by phosphorylation. PKA activation by dibutyryl cAMP in WT1-transfected cells resulted in the reversal of WT1 suppression of a reporter construct. Although WT1 protein is predominantly localized to the nucleus, this expression pattern is altered upon PKA activation, resulting in the cytoplasmic retention of WT1. Accordingly, phosphorylation may play a role in modulating the transcriptional regulatory activity of WT1 through interference with nuclear translocation, as well as by inhibition of WT1 DNA binding.
 ...
PMID:Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation. 889 54

The human G0/G1 switch (G0S) gene, G0S24, and its rodent immediate-early homolog (TIS11, TTP, NUP475) are part of a mammalian gene family whose members encode CCCH zinc finger domains and domains similar to part of the large subunit of RNA polymerase II and to the Mei2 regulator of G1 arrest in fission yeast. We compared the RNA expression of G0S24 with that of other G0S genes in cultured blood mononuclear cells and examined the levels of various RNA processing intermediates. Freshly isolated cells contained high levels of several G0S RNAs, which declined by 24 h, suggesting transient spontaneous stimulation during cell purification (Heximer et al., 1996). However, in cells preincubated for 24 h, G0S24 RNA levels remained much higher than those of other G0S genes (107+/-42 x 10(6) molecules/microg of RNA); stimulation with lectin (Con-A) further increased G0S24 RNA, much of which remained nuclear. Like those of FOS/G0S7, EGR1/G0S30 and of the gene encoding the regulator of G protein signalling 1 (RGS1), G0S24 RNA levels increased more in response to a protein kinase C activator than to a calcium ionophore, whereas the opposite held for FOSB/G0S3 and RGS2/G0S8. With appropriate PCR primer pairs, we showed a G0S24 RNA processing intermediate, which crossed the exon-1/intron boundary, and nonpolyadenylated nuclear RNA extending into the 3' flank, where there is a second CpG island. The concentration of the latter intermediate (1.2+/-0.2 x 10(6) molecules/microg of RNA), which increased transiently on cell stimulation, did not account for all G0S24 nuclear RNA. The levels of G0S24 RNA and both intermediates were increased by the protein synthesis inhibitor cycloheximide, consistent with regulation by a labile repressor.
 ...
PMID:Expression and processing of G0/G1 switch gene 24 (G0S24/TIS11/TTP/NUP475) RNA in cultured human blood mononuclear cells. 953 5

Expression of the LHbeta gene has been shown to be modulated by both the orphan nuclear receptor, steroidogenic factor-1 (SF-1), and the early growth response protein 1, Egr-1. It is also well known that LHbeta mRNA levels are increased after hormonal activation of the protein kinase C (PKC) signaling system, for example by GnRH; however, the mechanisms by which the PKC system exerts this effect has not been fully characterized. By transient transfection of the GH3 cell line, we demonstrate that activation of the PKC system with the phorbol ester, phorbol 12-myristate 13-acetate (PMA), increases activity of region -207/+5 of the rat LHbeta gene promoter (approximately 2-fold) and markedly augments SF-1-induced stimulation (95-fold in the presence of both factors vs. 13-fold for SF-1 alone). Mutation of the two previously identified Egr-1 sites not only prevents Egr-1 effects on the LHbeta gene promoter, but also eliminates the synergistic response to PMA and SF-1 together, findings that were confirmed in a longer construct spanning region -797/+5. In the gonadotrope-derived cell line, alphaT3-1, these mutations eliminate the GnRH responsiveness of the -207/+5 LHbeta promoter construct. We next show that PMA treatment (GH3 and alphaT3-1 cells) or GnRH treatment (alphaT3-1 cells) induces expression of Egr-1, as detected by Egr-1 interaction with Egr-1 DNA-binding sites in the rat LHbeta gene promoter sequence. Furthermore, we demonstrate that PMA increases steady-state Egr-1 mRNA levels via increased Egr-1 transcription. We conclude that PMA-induced stimulation of LHbeta gene expression is achieved, at least in part, by induction of Egr-1 expression.
 ...
PMID:The protein kinase C system acts through the early growth response protein 1 to increase LHbeta gene expression in synergy with steroidogenic factor-1. 989 16

GnRH regulation of LH secretion is well understood and involves Ca(2+) mobilization. However, the mechanism by which GnRH activates transcription of the LHbeta gene is controversial. GnRH is known to elevate intracellular calcium and activate the protein kinase C (PKC) pathway. The present study evaluated the pathway(s) involved in GnRH induction of LHbeta transcription. We have previously reported that the equine LHbeta (eLHbeta -448/+60) promoter is active in alphaT3-1 cells. Therefore, we created a clonal, stably transfected alphaT3-1 gonadotroph cell line harboring the eLHbeta promoter (-448/+60) fused to the luciferase reporter gene. Administration of a GnRH agonist resulted in induction of promoter activity that was completely inhibited by the antagonist antide. Various calcium-affecting drugs had no effect on the promoter. Administration of phorbol 12-myristate 13-acetate (PMA) elicited an activation similar to, albeit lower than, that with GnRH. Down-regulation or pharmacological inhibition of PKC completely blocked PMA's induction of the promoter, while GnRH induction was only partly attenuated. Treatment with the mitogen-activated protein kinase (MAPK) kinase inhibitor, PD98059, completely inhibited the activation of eLHbeta by PMA but only partly diminished GnRH's induction. Expression of the transcription factor, early growth response protein 1 (Egr1), correlated completely with activation of MAPK, suggesting that Egr1 is the factor through which PKC/MAPK acts. Our data suggest that GnRH induces activity of the eLHbeta promoter by activating a signal transduction cascade involving PKC-MAPK-Egr1 but that has no significant requirement for calcium.
 ...
PMID:Gonadotropin-releasing hormone activates the equine luteinizing hormone beta promoter through a protein kinase C/mitogen-activated protein kinase pathway. 1045 49

Gonadotropin-releasing hormone (GnRH) stimulates gonadotropin (GTH) subunit gene expression via G protein-coupled membrane receptors. GnRH-stimulated GTH subunit gene expression is mediated by protein kinase C (PKC) and Ca(2+) signaling pathways. Recent numerous reports on signal transduction pathways which are involved in GnRH stimulation of mammalian GTH subunit genes showed differential sensitivity of GTH subunit genes to the two signaling pathways. Our recent studies on salmon GTH (sGTH) IIbeta subunit gene showed that its stimulation by GnRH is dependent on the PKC pathway. Furthermore, gel retardation and mutagenesis studies suggested that pituitary homeo box 1 (Ptx1) and Sp1 mediate the GnRH-induced PKC signaling on the sGTHIIbeta gene. However, both PKC and Ca(2+) pathways are involved in the GnRH-stimulated GTH alpha and LHbeta genes. Different preference to the pathways were often reported in a certain GTH subunit gene in different circumstances, suggesting that molecular targets of the two signaling pathways are different. Ets-related factor and cAMP response element binding protein have been proposed as targets of GnRH signaling on GTH alpha genes. Sp1 and early growth response protein 1 play pivotal roles in GnRH-stimulated LHbeta gene expression in synergism with steroidogenic factor-1 and Ptx1. Activating protein-1 mediates GnRH-induced PKC signaling to stimulate FSHbeta gene expression. Therefore, divergent transcription factors are involved in GnRH stimulation of GTH subunit gene expression, and molecular mechanisms of GnRH stimulation may be partially conserved between sGTH IIbeta and mammalian LHbeta genes.
 ...
PMID:Signal transduction pathways and transcription factors involved in the gonadotropin-releasing hormone-stimulated gonadotropin subunit gene expression. 1139 88

Thrombospondin-1 (THBS1) is a large extracellular matrix glycoprotein that affects vasculature systems such as platelet activation, angiogenesis, and wound healing. Increases in THBS1 expression have been liked to disease states including tumor progression, atherosclerosis, and arthritis. The present study focuses on the effects of thrombin activation of the G-protein-coupled, protease-activated receptor-1 (PAR-1) on THBS1 gene expression in the microvascular endothelium. Thrombin-induced changes in gene expression were characterized by microarray analysis of approximately 11,000 different human genes in human microvascular endothelial cells (HMEC-1). Thrombin induced the expression of a set of at least 65 genes including THBS1. Changes in THBS1 mRNA correlated with an increase in the extracellular THBS1 protein concentration. The PAR-1-specific agonist peptide (TFLLRNK-PDK) mimicked thrombin stimulation of THBS1 expression, suggesting that thrombin signaling is through PAR-1. Further studies showed THBS1 expression was sensitive to pertussis toxin and protein kinase C inhibition indicating G(i/o)- and G(q)-mediated pathways. THBS1 up-regulation was also confirmed in human umbilical vein endothelial cells stimulated with thrombin. Analysis of the promoter region of THBS1 and other genes of similar expression profile identified from the microarray predicted an EBOX/EGRF transcription model. Expression of members of each family, MYC and EGR1, respectively, correlated with THBS1 expression. These results suggest thrombin formed at sites of vascular injury increases THBS1 expression into the extracellular matrix via activation of a PAR-1, G(i/o), G(q), EBOX/EGRF-signaling cascade, elucidating regulatory points that may play a role in increased THBS1 expression in disease states.
 ...
PMID:Thrombin modulates the expression of a set of genes including thrombospondin-1 in human microvascular endothelial cells. 1581 47

KEPI is a protein kinase C-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatases. We found no or reduced expression of KEPI in breast cancer cell lines, breast tumors and metastases in comparison to normal breast cell lines and tissues, respectively. KEPI protein expression and ubiquitous localization was detected with a newly generated antibody. Ectopic KEPI expression in MCF7 breast cancer cells induced differential expression of 95 genes, including the up-regulation of the tumor suppressors EGR1 (early growth response 1) and PTEN (phosphatase and tensin homolog), which is regulated by EGR1. We further show that the up-regulation of EGR1 in MCF7/KEPI cells is mediated by MEK-ERK signaling. The inhibition of this pathway by the MEK inhibitor UO126 led to a strong decrease in EGR1 expression in MCF7/KEPI cells. These results reveal a novel role for KEPI in the regulation of the tumor suppressor gene EGR1 via activation of the MEK-ERK MAPK pathway.
 ...
PMID:Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway. 1751 44


1 2 Next >>