Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipoprotein lipase (LPL), an enzyme which hydrolyzes triglycerides and participates in the catabolism of remnant lipoproteins, plays a crucial role in energy and lipid metabolism. The goal of this study was to analyze the expression and regulation of the LPL gene in human adrenals. Reverse transcriptase-polymerase chain reaction amplification and sequence analysis demonstrated the presence of LPL mRNA in fetal and adult human adrenal cortex. Furthermore, the human adrenocortical carcinoma cell line, NCI-H295, expresses LPL mRNA and protein, which is localized to the outer cellular membrane as demonstrated by immunofluorescence confocal microscopy and can be released in the medium by heparin addition. To asses whether the LPL gene is regulated by agents regulating adrenal steroidogenesis, NCI-H295 cells were treated with activators of second messenger systems. Whereas the calcium-ionophore A23187 did not affect LPL gene expression, treatment with phorbol 12-myristate 13-acetate decreased LPL mRNA levels in a time- and dose-dependent manner. This decrease after phorbol 12-myristate 13-acetate was associated with diminished heparin-releasable LPL mass and activity in the culture medium. Addition of the cAMP analog 8-Br-cAMP to NCI-H295 cells resulted in a rapid, but transient dose-dependent induction of LPL mRNA. Treatment with the protein synthesis inhibitor cycloheximide gradually induced, whereas simultaneous addition of cAMP and cycloheximide superinduced LPL mRNA levels. Nuclear run-on analysis indicated that the effects of cAMP and cycloheximide occurred at the transcriptional and post-transcriptional level, respectively. Transient co-transfection assays demonstrated that the first 230 base pairs of the proximal LPL promoter contain a cAMP-responsive element activated by protein kinase A and transcription factors belonging to the CREB/CREM family. These data indicate that LPL is expressed in human adrenal cortex and regulated in NCI-H295 adrenocortical carcinoma cells by activators of the protein kinase A and protein kinase C second messenger pathways in a manner comparable to P450scc, which catalyzes the first step in adrenal steroidogenesis. These observations suggest a role for LPL in adrenal energy and/or lipid metabolism and possibly in steroidogenesis.
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PMID:Expression and regulation of the lipoprotein lipase gene in human adrenal cortex. 866 37

The cAMP/protein kinase A signaling pathway activates the cAMP-responsive transcription factor CREB. Here we describe a unique alternative RNA splicing event that occurs during the development of germ cells in the testis, resulting in a translational switch from an mRNA encoding activator CREB to an mRNA encoding novel inhibitor CREB isoforms (I-CREBs). Alternative splicing of an additional exon into the CREB mRNA in mid to late pachytene spermatocytes results in the premature termination of translation and consequent downstream reinitiation of translation producing I-CREBs. The I-CREBs down-regulate cAMP-activated gene expression by inhibiting activator CREB from binding to cAMP response elements. Further, the developmental stage-specific expression of I-CREBs in germ cells of the seminiferous tubules correlates with the cyclical down-regulation of activator CREB, suggesting that I-CREBs repress expression of the cAMP-inducible CREB gene as well as other genes transiently induced by cAMP during the 12-day cycle of spermatogenesis.
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PMID:Alternative exon splicing controls a translational switch from activator to repressor isoforms of transcription factor CREB during spermatogenesis. 870 38

Membrane depolarization, or agents which increase intracellular calcium, elicit transcriptional activation of tyrosine hydroxylase (TH). In this study we analyze the factors involved in the regulation of the TH promoter by a calcium ionophore. PC12 cells were transiently transfected with plasmids containing wild type or mutated 5' flanking sequences of the rat TH gene, fused to bacterial chloramphenicol acetyl transferase (CAT). Point mutations introduced into the consensus cAMP-regulatory element (CRE) abolished the induction of CAT by ionomycin indicating that it is essential for mediating the calcium response. An intact and functional AP1 site did not confer calcium inducibility when the CRE/CaRE sequence was mutated. The extent and kinetics of the increase in intracellular calcium as well as the induction of CAT activity under the control of TH promoter by ionomycin were similar in PC12 cells and in the A123.7, protein kinase A (PKA) deficient cell line. In both cell lines addition of ionomycin rapidly increased the phosphorylation of transcription factor CREB at Ser-133. These results suggest that the activation of TH transcription by ionomycin does not require PKA. However, KN62 an inhibitor of Ca2+/calmodulin dependent (CaM) kinases prevented the induction indicating possible involvement of CAM kinases in the calcium response.
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PMID:Promoter elements and second messenger pathways involved in transcriptional activation of tyrosine hydroxylase by ionomycin. 871 52

Transcription of a number of eukaryotic genes is activated in response to an increase in the intracellular cAMP concentration. These genes stimulated by cAMP have a common promoter element, cAMP response element (CRE). The CRE is recognized by a CRE binding protein, CREB. The binding of CREB to CRE does not induce transcription. Activation of transcription requires the phosphorylation or CREB at Ser-133. In the case of the cAMP pathway, the activated catalytic subunit of cAMP-dependent protein kinase (PKA) translocates to the nucleus and phosphorylates Ser-133 of CREB. In the nervous system, signals transmitted across synapses are known to regulate gene expression in the post-synaptic cell. This process often involves membrane depolarization and subsequent amplification of intracellular Ca2+. The transcriptional activation induced by membrane depolarization and Ca2+ influx is mediated by a promoter element, called the Ca(2+)-responsive element (CaRE). Recent studies of c-fos and proenkephalin gene expression have shown that the CaRE is indistinguishable from a CRE. In this paper, we focus on the possible interactions between Ca2+ and the cAMP signaling pathways into the nucleus.
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PMID:[Transcriptional regulation by cAMP and calcium]. 872 Oct 7

Studies in Aplysia californica indicate that cAMP-mediated gene expression is necessary for long-term facilitation, a correlate of long-term memory. It has been shown that blocking the expression of cAMP-inducible genes in sensory neurons impedes long-term facilitation without any effect on short-term facilitation. Specifically, blocking the binding of CREB-like proteins or inhibiting the expression of a cAMP-inducible gene, C[symbon: see text]EBP, impairs long-term facilitation. In this report, we show the presence of a family of CREB-like proteins in Aplysia CNS that specifically bind to the CRE sequence and cross-react with rat CREB antibodies. Similar to mammalian CREB proteins, Aplysia homologues interact with each other via leucine zipper domains. This interaction can be disrupted by peptides containing the CREB leucine zipper sequence. We demonstrate that a 43 kDa CREB-like protein present in CNS extracts can be phosphorylated in vitro by cAMP-dependent protein kinase A. Moreover, exposure of ganglia to serotonin (5-HT), a transmitter involved in long-term facilitation, increases the phosphorylation of this protein. This biochemical data further supports the involvement of CREB-like proteins in memory storage.
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PMID:Characterization and phosphorylation of CREB-like proteins in Aplysia central nervous system. 880 12

Members of the CREB/CREM/ATF family of transcription factors either enhance or repress transcription after binding to the cAMP response elements (CREs) of numerous genes. The rat gene for tyrosine hydroxylase (TH) bears a canonical CRE, at base pairs -38 through -45 from the transcription initiation site, that is essential for basal and cAMP-stimulated transcription (Kim, K.-S., Lee, M. K., Carroll, J., and Joh, T. H. (1993) J. Biol. Chem. 268, 15689-15695; Lazaroff, M., Patankar, S., Yoon, S. O., and Chikaraishi, D. M. (1995) J. Biol. Chem. 270, 21579-21589). The current study identifies CRE-binding proteins induced in pharmacological paradigms characterized by TH activation. PC12- and rat adrenal gland-derived nuclear proteins retarded a TH-CRE oligonucleotide in gel mobility shift assays with virtually identical patterns. These differed substantially from patterns exhibited by extracts from locus ceruleus or from neuroblastoma (SK-N-BE()C) and locus ceruleus-derived (CATH.a) cell lines. Forskolin stimulation of PC12 cells and reserpine treatment of rats increased, in nuclear extracts derived from cells and adrenal glands, respectively, the amount of a fast moving CRE/protein complex that was supershifted by an anti-CREM antibody. Subsequent Western, Northern, and polymerase chain reaction analyses indicated that a specific member of the CREM family, the inducible cAMP early repressor (ICER), was strongly induced in both systems. Cotransfection of PC12 cells with TH2400CAT plasmid and the expression vector pCMV-ICER-Ib demonstrated that ICER efficiently represses the transcriptional activity of the TH gene promoter. In addition, PKA-stimulated transcriptional activity of the promoter was effectively suppressed by ICER. These results suggest that ICER can modulate cAMP-stimulated transcription of the TH gene and provide a model accounting for rapid reversal of increased TH transcription following elevations in cAMP.
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PMID:Inducible cAMP early repressor can modulate tyrosine hydroxylase gene expression after stimulation of cAMP synthesis. 881 Mar 3

Engagement of surface immunoglobulin on mature B cells leads to rescue from apoptosis and to proliferation. Levels of bcl-2 mRNA and protein increase with cross-linking of surface immunoglobulin. We have located the major positive regulatory region for control of bcl-2 expression in B cells in the 5'-flanking region. The positive region can be divided into an upstream and a downstream regulatory region. The downstream regulatory region contains a cyclic AMP-responsive element (CRE). We show by antibody supershift experiments and UV cross-linking followed by denaturing polyacrylamide gel electrophoresis that both CREB and ATF family members bind to this region in vitro. Mutations of the CRE site that result in loss of CREB binding also lead to loss of functional activity of the bcl-2 promoter in transient-transfection assays. The presence of an active CRE site in the bcl-2 promoter implies that the regulation of bcl-2 expression is linked to a signal transduction pathway in B cells. Treatment of the mature B-cell line BAL-17 with either anti-immunoglobulin M or phorbol 12-myristate 13-acetate leads to an increase in bcl-2 expression that is mediated by the CRE site. Treatment of the more immature B-cell line, Ramos, with phorbol esters rescues the cells from calcium-dependent apoptosis. bcl-2 expression is increased following phorbol ester treatment, and the increased expression is dependent on the CRE site. These stimuli result in phosphorylation of CREB at serine 133. The phosphorylation of CREB that results in activation is mediated by protein kinase C rather than by protein kinase A. Although the CRE site is necessary, optimal induction of bcl-2 expression requires participation of the upstream regulatory element, suggesting that phosphorylation of CREB alters its interaction with the upstream regulatory element. The CRE site in the bcl-2 promoter appears to play a major role in the induction of bcl-2 expression during the activation of mature B cells and during the rescue of immature B cells from apoptosis. It is possible that the CRE site is responsible for induction of bcl-2 expression in other cell types, particularly those in which protein kinase C is involved.
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PMID:Induction of bcl-2 expression by phosphorylated CREB proteins during B-cell activation and rescue from apoptosis. 881 67

We have evaluated the signaling pathways activated by parathyroid hormone (PTH) in SaOS2 human osteoblastlike cells correlating with induction of the c-fos proto-oncogene. Human PTH(1-34) (hPTH[1-34]) and hPTH(1-34) Nle8,18 Tyr34 induced the expression of c-fos mRNA in quiescent SaOS2 cells in a concentration-dependent manner. N-terminal truncations of hPTH(1-34) that fail to activate protein kinase A (PKA) also abolished c-fos mRNA induction. In gel retardation assays hPTH(1-34) led to a change in the mobility of specific, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-containing protein-DNA complexes identical to that caused by other activators of PKA. The appearance of this altered mobility complex correlated temporally with the induction of c-fos mRNA. Using a c-fos serum response element probe, a slowed protein DNA complex appeared upon serum, epidermal growth factor, and basic fibroblast growth factor treatment. This slowed complex reflects phosphorylation of the transcription factor ternary complex factor (TCF) mediated via activation of the mitogen-activated protein (MAP) kinase pathway. The MAP kinase cascade is also activated by protein kinase C (PKC), and treatment with phorbol ester led to the induced TCF shift. In contrast, PTH did not produce this shift, ruling out PTH activation of c-fos via PKC and the MAP kinase signaling cascade. Further evidence for this was the lack of effect of the highly selective PKC inhibitor CGP 41251 on c-fos induction by hPTH(1-34). The janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling cascade targets the v-sis-inducible element in the c-fos promoter via the induced binding of STATs. Interferon gamma rapidly induced STAT binding in SaOS2 cells, unlike PTH. Thus, PTH induction of c-fos transcription appears to occur principally through activation of PKA that then targets CREB and the c-fos calcium/cAMP response element.
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PMID:Analysis of signaling pathways used by parathyroid hormone to activate the c-fos gene in human SaOS2 osteoblast-like cells. 885 42

Fibroblast growth factor (FGF) activates a protein kinase cascade in SK-N-MC cells that regulates gene expression at a cyclic-AMP response element (CRE) by stimulating the transcriptional activity of CREB. The activation of CREB is prevented by a dominant negative mutant of Ras and triggered via the same site (Ser133) that becomes phosphorylated in response to cyclic AMP and Ca2+. However, the effect of FGF is not mediated by cyclic AMP-dependent protein kinase, TPA-sensitive isoforms of protein kinase-C, p70S6K or p90rsk (all of which phosphorylate CREB at Ser133 in vitro). Instead, we identify the FGF-stimulated CREB kinase as MAP kinase-activated protein (MAPKAP) kinase-2, an enzyme that lies immediately downstream of p38 MAP kinase, in a pathway that is also stimulated by cellular stresses. We show that MAPKAP kinase-2 phosphorylates CREB at Ser133 in vitro, that the FGF- or stress-induced activation of MAPKAP kinase-2 and phosphorylation of CREB and ATF-1 are prevented by similar concentrations of the specific p38 MAP kinase inhibitor SB 203580, and that MAPKAP kinase-2 is the only detectable SB 203580-sensitive CREB kinase in SK-N-MC cell extracts. We also show that transfection of RK/p38 MAP kinase in SK-N-MC cells, but not transfection of p44 MAP kinase, activates Gal4-CREB-dependent transcription via Ser133. These findings identify a new growth factor and stress-activated signaling pathway that regulates gene expression at the CRE.
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PMID:FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. 888 54

CREB-binding protein (CBP) functions as a coactivator molecule for a number of transcription factors including CREB, c-Fos, c-Jun, c-Myb, and several nuclear receptors. Although binding sites for these factors within CBP have been identified, the regions of CBP responsible for transcriptional activation are unknown. In this report, we show that the N-terminal half of CBP is sufficient for activation of CREB-mediated transcription and that this region contains a strong transcriptional activation domain (TAD). Both deletion of this TAD or sequestering of factors that the TAD binds using a squelching assay were found to greatly decrease the ability of CBP to activate CREB-mediated transcription. In vivo studies by others have shown that p300/CBP associates with TBP; using an in vitro approach, we show the N-terminal TAD binds TBP. We also examined the ability of the C terminus of CBP to activate transcription using GAL-CBP chimeras. With this approach, we identified two C-terminal TADs located adjacent to the c-Fos binding site. In previous studies, cAMP-dependent protein kinase A (PKA) increased the transcriptional activity of a GAL full-length CBP chimera in F9 cells, and of the C terminus in PC-12 cells. Here, we demonstrate that PKA also increased the ability of the N-terminal TADs of CBP to activate transcription in PC-12 but not F9 or COS-7 cells, suggesting that this PKA-responsiveness is cell type-specific.
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PMID:CREB-binding protein activates transcription through multiple domains. 891 Apr 28


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