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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulsatile secretion of GnRH is the major regulator of gonadotropin (LH, FSH) gene expression and secretion. Recently, GnRH has been shown to rapidly stimulate the expression of early growth response protein-1 (Egr-1), a transcription factor that is essential for LHbeta gene expression in the pituitary. In this study, we examined the regulatory elements and signal transduction pathways by which GnRH regulates Egr-1 transcription. Deletion analysis of the murine Egr-1 promoter identified two regions (-370 to -342 and -116 to -73) that are critical for GnRH responsiveness in alphaT3 pituitary gonadotrope cells. The first region, which contains two serum response elements (SREs), contributed about 70-80% of GnRH inducibility, whereas the second region, which contains two SREs and one Ets binding site, conferred an additional 20-30% of activity. Mutations that abolish protein binding to these SREs and Ets binding sites completely eliminated GnRH-mediated transcriptional activation of the Egr-1 promoter. Mutation of cAMP response element reduced promoter activity by 40%. Using specific protein kinase inhibitors, GnRH stimulation of Egr-1 expression was found to be dependent on PKC/ERK pathways. In addition, GnRH activated p90 ribosomal S6 kinase, which has the potential to phosphorylate serum response factor and cAMP response element binding protein. We conclude that GnRH stimulation of Egr-1 gene expression requires several distinct SREs/Ets elements and a cAMP response element and is mediated via activation of PKC/ERK signaling pathways.
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PMID:GnRH regulates early growth response protein 1 transcription through multiple promoter elements. 1181 96

In normal human melanocytes various mitogens activate the mitogen-activated protein kinases ERK1/2 and the downstream transcription factor CREB (Ca2+/cAMP response element binding protein). Endothelin-1, basic fibroblast growth factor, and alpha-melanotropin interact synergistically to stimulate human melanocyte proliferation. The former two mitogens phosphorylated ERK1/2, its substrate p90rsk, and CREB. Alpha-melanotropin, forskolin, or dibutyryl cAMP failed to phosphorylate any of those targets, however. The concomitant presence of endothelin-1, basic fibroblast growth factor, and alpha-melanotropin significantly potentiated CREB phosphorylation. The mitogen-induced phosphorylation of p90rsk and CREB was dependent on ERK1/2 activation, and was mediated by intracellular calcium mobilization and by protein kinase C and tyrosine kinase activation, but not by activation of the cAMP-dependent protein kinase A. Exposure of melanocytes to ultraviolet radiation B resulted in the phosphorylation of the stress-induced mitogen- activated protein kinases p38 and JNK/SAPK, but not ERK1/2. Ultraviolet radiation B induced the phosphorylation of CREB via a pathway that was partially dependent on p38, but had no effect on p90rsk or ERK1/2. Therefore, in human melanocytes, CREB is a common downstream target for distinct effectors that are involved in either mitogenic signaling or stress signaling initiated by ultraviolet radiation B.
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PMID:Mitogen- and ultraviolet-B-induced signaling pathways in normal human melanocytes. 1184 50

In the mammalian testis, the binding of FSH to Sertoli cells activates the cAMP-dependent protein kinase A signaling pathway, resulting in the phosphorylation of the cAMP response element binding protein (CREB). Previous studies have also shown that CREB gene expression is activated by cAMP in Sertoli cells and that 2 cAMP response elements (CREs) that bind CREB and a neighboring Sp1 binding site are required for basal and cAMP-inducible CREB promoter activity. In contrast, CREB expression has been less well characterized in testis germ cells. We demonstrated that CREB and Sp1 are expressed in early germ cells only through the midpachytene stage of spermatogenesis. Furthermore, CREB promoter activity was induced over 70-fold by transient overexpression of Sp1 in SL2 cells, suggesting that Sp1 is an important regulator of CREB expression. Further studies of the CREB promoter revealed an additional regulatory element in the -130 region between the Sp1 and CREB transcription factor binding sites that is necessary for full promoter activity. Proteins expressed in Sertoli cells and germ cells bind specifically to the newly identified regulatory region. These studies suggest that proteins binding to Sp1 motifs and the -130 region are required to activate the CREB promoter.
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PMID:Regulation of cyclic adenosine 3',5'-monophosphate response element binding protein (CREB) expression by Sp1 in the mammalian testis. 1187 72

Neurogranin (Ng) is a brain-specific, postsynaptically located protein kinase C (PKC) substrate, highly expressed in the cortex, hippocampus, striatum, and amygdala. This protein is a Ca(2+)-sensitive calmodulin (CaM)-binding protein whose CaM-binding affinity is modulated by phosphorylation and oxidation. To investigate the role of Ng in neural function, a strain of Ng knockout mouse (KO) was generated. Previously we reported (Pak, J. H., Huang, F. L., Li, J., Balschun, D., Reymann, K. G., Chiang, C., Westphal, H., and Huang, K.-P. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 11232-11237) that these KO mice displayed no obvious neuroanatomical abnormality, but exhibited deficits in learning and memory and activation of Ca(2+)/CaM-dependent protein kinase II. In this report, we analyzed several downstream phosphorylation targets in phorbol 12-myristate 13-acetate- and forskolin-treated hippocampal slices from wild type (WT) and KO mice. Phorbol 12-myristate 13-acetate caused phosphorylation of Ng in WT mice and promoted the translocation of PKC from the cytosolic to the particulate fractions of both the WT and KO mice, albeit to a lesser extent in the latter. Phosphorylation of downstream targets, including mitogen-activated protein kinases, 90-kDa ribosomal S6 kinase, and the cAMP response element binding protein (CREB) was significantly attenuated in KO mice. Stimulation of hippocampal slices with forskolin also caused greater stimulation of protein kinase A (PKA) in the WT as compared with those of the KO mice. Again, phosphorylation of the downstream targets of PKA was attenuated in the KO mice. These results suggest that Ng plays a pivotal role in regulating both PKC- and PKA-mediated signaling pathways, and that the deficits in learning and memory of spatial tasks detected in the KO mice may be the result of defects in the signaling pathways leading to the phosphorylation of CREB.
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PMID:Attenuation of protein kinase C and cAMP-dependent protein kinase signal transduction in the neurogranin knockout mouse. 1191 90

We have evaluated the importance of the Ser/Thr protein phosphorylation and dephosphorylation for chondrogenesis in high-density chicken limb bud mesenchymal cell cultures (HDCs) by using H89, a cell-permeable protein kinase inhibitor, and okadaic acid (OA), a phosphoprotein phosphatase (PP)-specific inhibitor molecule. When 20 nM OA was applied to the HDCs on Days 2 and 3 of culturing, it significantly inhibited protein phosphatase 2A (PP2A), enhanced cartilage formation, and elevated the activity of cAMP-dependent protein kinase (PKA). Application of 20 microM H89 significantly decreased the activity of PKA and blocked the chondrogenesis in HDCs. Furthermore, OA enhanced cartilage formation and elevated the suppressed activity of PKA even in the H89-pretreated HDCs. cGMP-dependent protein kinase was not detected in HDCs, while protein kinase Cmu (PKCmu), which is also inhibited by nanomolar concentrations of H89, was present throughout the culturing period. Neither OA nor H89 influenced the expression of the catalytic subunit of PKA or the cAMP response element binding protein, CREB. However, a significantly elevated amount of Ser-133-phosphorylated-CREB (P-CREB) was detected following addition of OA, while H89 treatment resulted in a decrease of the amount of P-CREB. Our results demonstrate that PP2A plays a role in the regulation of the PKA signaling pathway and that the phosphorylation level of CREB is influenced by the activity of both enzymes during in vitro chondrogenesis.
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PMID:Protein phosphatase 2A is involved in the regulation of protein kinase A signaling pathway during in vitro chondrogenesis. 1192

We have recently demonstrated protection against renal ischemic-reperfusion injury in vivo by A(1)- and A(2a)-adenosine receptor (AR) modulations. To further elucidate the signaling cascades of AR-induced cytoprotection against reperfusion/oxidant-mediated injury, immortalized human proximal tubule (HK-2) cells were treated with H(2)O(2). H(2)O(2) caused dose- and time-dependent HK-2 cell death that was measured by lactate dehydrogenase release and trypan blue dye uptake. Adenosine protected against H(2)O(2)-induced HK-2 cell death by means of A(1)- and A(2a)-AR activation. A(1)-AR-mediated protection involves pertussis toxin-sensitive G proteins and protein kinase C, whereas A(2a)-AR-mediated protection involves protein kinase A activation by means of cAMP and activation of the cAMP response element binding protein. Moreover, protein kinase A activators (forskolin and Sp-isomer cAMP) also protected HK-2 cells against H(2)O(2) injury. De novo gene transcription and protein synthesis are required for both A(1)- and A(2a)-AR-mediated cytoprotection as actinomycin D and cycloheximide, respectively, blocked cytoprotection. Chronic treatments with a nonselective AR agonist abolished the protection by adenosine. Moreover, chronic treatments with a nonselective AR antagonist increased the endogenous tolerance of HK-2 cells against H(2)O(2). We concluded that A(1)- and A(2a)-AR activation protects HK-2 cells against H(2)O(2)-induced injury by means of distinct signaling pathways that require new gene transcription and new protein synthesis.
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PMID:Adenosine attenuates oxidant injury in human proximal tubular cells via A(1) and A(2a) adenosine receptors. 1193 94

The double-stranded (ds) RNA-dependent protein kinase (PKR) is a primary regulator of antiviral responses; however, the ability of dsRNA to activate nuclear factor-kappa B (NF-kappa B) and dsRNA + interferon gamma (IFN-gamma) to stimulate inducible nitric-oxide synthase (iNOS) expression by macrophages isolated from PKR(-/-) mice suggests that signaling pathways in addition to PKR participate in antiviral activities. We have identified a novel phospholipid-signaling cascade that mediates macrophage activation by dsRNA and viral infection. Bromoenol lactone (BEL), a selective inhibitor of the calcium-independent phospholipase A(2) (iPLA(2)), prevents dsRNA- and virus-induced iNOS expression by RAW 264.7 cells and mouse macrophages. BEL does not modulate dsRNA-induced interleukin 1 expression, nor does it affect dsRNA-induced NF-kappa B activation. Protein kinase A (PKA) and the cAMP response element binding protein (CREB) are downstream targets of iPLA(2), because selective PKA inhibition prevents dsRNA-induced iNOS expression, and the inhibitory actions of BEL on dsRNA-induced iNOS expression are overcome by the direct activation of PKA. In addition, BEL inhibits dsRNA-induced CREB phosphorylation and CRE reporter activation. PKR does not participate in iPLA(2) activation or iNOS expression, because dsRNA stimulates iPLA(2) activity and dsRNA + IFN-gamma induces iNOS expression and nitric oxide production to similar levels by macrophages isolated from PKR(+/+) and PKR(-/-) mice. These findings support a PKR-independent signaling role for iPLA(2) in the antiviral response of macrophages.
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PMID:Novel role for calcium-independent phospholipase A(2) in the macrophage antiviral response of inducible nitric-oxide synthase expression. 1216 50

Jansen's metaphyseal chondrodysplasia (JMC) is an autosomal dominant disorder characterized by short-limbed dwarfism, delayed ossification, and hypercalcemia. Activating mutations in the PTH/PTHrP receptor have been identified as the molecular cause of this disorder. Although these mutations have been shown to increase cAMP accumulation, little is known about possible target genes of the downstream signaling pathways that may contribute to the pathogenesis of the disease. Here we demonstrate that JMC mutations of the PTH/PTHrP receptor induce activation of the cyclin D1 and cyclin A promoters in primary mouse chondrocytes and rat chondrosarcoma cells. Induction of cyclin D1 expression is required for stimulation of E2F-dependent transcription by mutant receptors. Activation of the cyclin D1 and cyclin A promoters requires a functional cAMP response element in both genes. Inhibition of protein kinase A or the transcription factor cAMP response element binding protein blocks the stimulation of both promoters by mutant receptors, whereas inhibition of activating transcription factor 2, c-Fos, or c-Jun has only minor effects. In summary, our data suggest that stimulation of cell cycle gene expression and cell cycle progression by mutant PTH/PTHrP receptors contribute to the pathogenesis of JMC.
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PMID:The cyclin D1 and cyclin A genes are targets of activated PTH/PTHrP receptors in Jansen's metaphyseal chondrodysplasia. 1219 52

The major protein component of the cornified cell envelope barrier structure of the epidermis is loricrin, and it is expressed late during terminal differentiation in epidermal keratinocytes. We have previously shown that an AP1 site located in the proximal promoter region (position -55) is essential for human loricrin promoter activity (Rossi, A., Jang, S-I., Ceci, R., Steinert, P. M., and Markova, N. G. (1998) J. Invest. Dermatol. 110, 34-40). In this study we show that its regulation requires complex cooperative and competitive interactions between multiple transcription factors in keratinocytes located in different compartments of the epidermis. We show that as few as 154 base pairs of 5'-upstream sequences from the cap site can direct the keratinocyte-specific expression in cultured keratinocytes. Mutation and DNA-protein analyses show that Sp1, c-Jun, an unidentified regulator, and the co-activator p300/CREB-binding protein up-regulate whereas Sp3, CREB-1/CREMalpha/ATF-1, Jun B, and an AP2-like protein (termed the keratinocyte-specific repressor-1 (KSR-1)) suppress loricrin promoter activity. We show that CREB protein can compete with c-Jun for the AP1 site and repress loricrin promoter activity. We show here that the protein kinase A pathway can activate loricrin expression by manipulation of the Sp1, Sp3, and KSR-1 levels in the nucleus. Thus, in undifferentiated cells, loricrin expression is suppressed by Jun B, Sp3, and KSR-1 proteins. But in advanced differentiated cells, levels of Sp3, KSR-1, and CREB proteins are lower; the unidentified regulator protein can bind; Sp1 and c-Jun are increased; and then p300/CBP is recruited. Together, these events allow loricrin transcription to proceed. Indeed, the synergistic effects of the Sp1, c-Jun, and p300 factors indicate that p300/CBP might act as bridge to form an active transcription complex.
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PMID:Loricrin expression in cultured human keratinocytes is controlled by a complex interplay between transcription factors of the Sp1, CREB, AP1, and AP2 families. 1220 Apr 29

Mesangial cell proliferation is an early event in several progressive renal diseases. When mesangial cells in culture are rendered quiescent by serum starvation and subsequently stimulated to proliferate, induction of c-fos is an early indicator of entry into the cell cycle. Several heparin-sensitive signals transduce these events. We have examined the potential roles of CaMK and PKA. Selective stimulation of CaMK with Ca(2+) ionophores and of PKA with forskolin or dibutyryl cAMP both result in induction of c-fos mRNA. CaMK but not PKA signaling is suppressed by low concentrations of heparin. Cross talk between the pathways has been demonstrated in some cells, with evidence of CaMK phosphorylating cAMP response element binding protein (CREB) at an inhibitory site and PKA suppressing CaMK-dependent signaling. However, in the present study, both pathways phosphorylated CREB on Ser(133) and induced c-fos in an additive manner. Serum, ionomycin, and forskolin all caused a rapid decline in cyclin D1 levels, but only serum effected a subsequent increase, indicative of cell cycle progression. We conclude that, in human mesangial cells, CaMK and PKA can both contribute to cell cycle entry, and, although induction of c-fos by CaMK requires active PKA, neither pathway antagonizes or synergizes c-fos induction by the other.
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PMID:Ca(2+)/calmodulin-dependent and cAMP-dependent kinases in induction of c-fos in human mesangial cells. 1237 63


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