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)

Addition of glucose to starved yeast cells elicits a dramatic restructuring of the transcriptional and metabolic state of the cell. While many components of the signaling network responsible for this response have been identified, a comprehensive view of this network is lacking. We have used global analysis of gene expression to assess the roles of the small GTP-binding proteins, Ras2 and Gpa2, in mediating the transcriptional response to glucose. We find that 90% of the transcriptional changes in the cell attendant on glucose addition are recapitulated by activation of Ras2 or Gpa2. In addition, we find that protein kinase A (PKA) mediates all of the Ras2 and Gpa2 transcriptional effects. However, we also find that most of the transcriptional effects of glucose addition to wild-type cells are retained in strains containing a PKA unresponsive to changes in cAMP levels. Thus, most glucose-responsive genes are regulated redundantly by a Ras/PKA-dependent pathway and by one or more PKA-independent pathways. Computational analysis extracted RRPE/PAC as the major response element for Ras and glucose regulation and revealed additional response elements mediating glucose and Ras regulation. These studies provide a paradigm for extracting the topology of signal transduction pathways from expression data.
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PMID:Ras and Gpa2 mediate one branch of a redundant glucose signaling pathway in yeast. 1513 98

Laryngeal carcinoma (LC) is the most commonly diagnosed malignancy and recently the incidence of this disease has increased. By means of the mRNA differential display method we identified a cDNA, Laryngeal carcinoma related gene 1 (LCRG1) which has significantly reduced expression in 40% (12/30) of primary LCs and in 6 of 10 various cancer cell lines. Northern Blot analysis showed that LCRG1 was expressed more abundantly in human heart, pancreas, skeletal muscle, and in murine testis, liver, brain and heart than in other tissues. The cDNA sequence of this gene is identical to part of the sequence of PAC HCIT75G16 clone (GenBank accession No. AC003042) from the chromosome band 17q12-21.1 which is one of the most common loss of heterozygosity (LOH) regions involved in LC, prostate cancer, etc. This gene is composed of six exons and spans about 60 kb of genomic DNA with a 3.4 kb mature transcript. The alignment of this gene with STS markers localized the gene to the previously identified tumor-suppressor locus D17S800-D17S930. The putative protein encoded by this gene is 288 amino acid with one potential site for phosphorylation by casein kinase II and no significant homology to any known proteins in the public databases. The primary tumor suppressive functions (proliferation rate,soft agar growth and tumor formation) were observed in a LC cell line (Hep-2) by lipofectin transfection. Together these data strongly suggest a potential role of LCRG1 contributing to the development of LC.
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PMID:Molecular cloning and characterization of LCRG1 a novel gene localized to the tumor suppressor locus D17S800-D17S930. 1514 23

Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca(2+) entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca(2+) or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC(1) receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca(2+) entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) as a growth hormone (GH)-releasing factor in grass carp. I. Functional coupling of cyclic adenosine 3',5'-monophosphate and Ca2+/calmodulin-dependent signaling pathways in PACAP-induced GH secretion and GH gene expression in grass carp pituitary cells. 1612 57

Hepatitis C is an important blood borne infection caused by hepatitis C virus (HCV). Chronic inflammation induced by this viral infection and its role in carcinogenesis are well recognized. The treatment of HCV infection has developed enormously over recent years and is believed to be a good way for stopping of carcinogenesis process. However, mutation of the virus is an important factor that can bring drug resistance. Presently, prediction of protein nanostructure and function is a great challenge in the proteomics and structural genomics era. To identify points which are vulnerable to mutation is a new trend to expand the knowledge at the genomic and proteomic levels Here, the author performed a bioinformatic analysis to determine positions that trend to comply with peptide motifs in the amino acid sequence of HCV protein kinase -eIF2-alpha phosphorylation homology domain (PePHD). To identify weak linkage in HCV PePHD, a new bioinformatic tool, GlobPlot, was used. Positions 2-7, 29-39, 53-57, 90-98, 123-133, 202-227, 324-355, 439-448 were identified as positions resistant to mutation. Some are already known and others are newly discovered. Based on this study, weak linkages in HCV PePHD could be identified and can be good information for expectation of possible new mutations that can lead to failure of HCV therapy. In addition, the results from this study can be good information for further research on the diagnosis for mutants HCV and vaccine development.
Asian Pac J Cancer Prev
PMID:Weak linkage in hepatitis C PePHD: identification of mutation prone point that can lead to failure of antiviral therapy for prevention of hepatocellular carcinoma. 1747 90

Pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient mice are prone to sudden neonatal death and have reduced respiratory response to hypoxia. Here we found that PACAP-38 elevated cytosolic [Ca(2+)] ([Ca(2+)](i)) in the oxygen sensing type I cells but not the glial-like type II (sustentacular) cells of the rat carotid body. This action of PACAP could not be mimicked by vasoactive intestinal peptide but was abolished by PACAP 6-38, implicating the involvement of PAC(1) receptors. H89, a protein kinase A (PKA) inhibitor attenuated the PACAP response. Simultaneous measurement of membrane potential and [Ca(2+)](i) showed that the PACAP-mediated [Ca(2+)](i) rise was accompanied by depolarization and action potential firing. Ni(2+), a blocker of voltage-gated Ca(2+) channels (VGCC) or the removal of extracellular Ca(2+) reversibly inhibited the PACAP-mediated [Ca(2+)](i) rise. In the presence of tetraethylammonium (TEA) and 4-aminopyridine (4-AP), PACAP reduced a background K(+) current. Anandamide, a blocker of TWIK-related acid-sensitive K(+) (TASK)-like K(+) channel, occluded the inhibitory action of PACAP on K(+) current. We conclude that PACAP, acting via the PAC(1) receptors coupled PKA pathway inhibits a TASK-like K(+) current and causes depolarization and VGCC activation. This stimulatory action of PACAP in carotid type I cells can partly account for the role of PACAP in respiratory disorders.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates the oxygen sensing type I (glomus) cells of rat carotid bodies via reduction of a background TASK-like K+ current. 1749 41

The intracellular signaling pathways mediating the neurotrophic actions of pituitary adenylate cyclase-activating polypeptide (PACAP) were investigated in human neuroblastoma SH-SY5Y cells. Previously, we showed that SH-SY5Y cells express the PAC(1) and VIP/PACAP receptor type 2 (VPAC(2)) receptors, and that the robust cAMP production in response to PACAP and vasoactive intestinal peptide (VIP) was mediated by PAC(1) receptors (Lutz et al. 2006). Here, we investigated the ability of PACAP-38 to differentiate SH-SY5Y cells by measuring morphological changes and the expression of neuronal markers. PACAP-38 caused a concentration-dependent increase in the number of neurite-bearing cells and an up-regulation in the expression of the neuronal proteins Bcl-2, growth-associated protein-43 (GAP-43) and choline acetyltransferase: VIP was less effective than PACAP-38 and the VPAC(2) receptor-specific agonist, Ro 25-1553, had no effect. The effects of PACAP-38 and VIP were blocked by the PAC(1) receptor antagonist, PACAP6-38. As observed with PACAP-38, the adenylyl cyclase activator, forskolin, also induced an increase in the number of neurite-bearing cells and an up-regulation in the expression of Bcl-2 and GAP-43. PACAP-induced differentiation was prevented by the adenylyl cyclase inhibitor, 2',5'-dideoxyadenosine (DDA), but not the protein kinase A (PKA) inhibitor, H89, or by siRNA-mediated knock-down of the PKA catalytic subunit. PACAP-38 and forskolin stimulated the activation of extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAP; p38 MAP kinase) and c-Jun N-terminal kinase (JNK). PACAP-induced neuritogenesis was blocked by the MEK1 inhibitor PD98059 and partially by the p38 MAP kinase inhibitor SB203580. Activation of exchange protein directly activated by cAMP (Epac) partially mimicked the effects of PACAP-38, and led to the phosphorylation of ERK but not p38 MAP kinase. These results provide evidence that the neurotrophic effects of PACAP-38 on human SH-SY5Y neuroblastoma cells are mediated by the PAC(1) receptor through a cAMP-dependent but PKA-independent mechanism, and furthermore suggest that this involves Epac-dependent activation of ERK as well as activation of the p38 MAP kinase signaling pathway.
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PMID:PACAP-38 induces neuronal differentiation of human SH-SY5Y neuroblastoma cells via cAMP-mediated activation of ERK and p38 MAP kinases. 1799 38

HPV-16 is the HPV most often linked to cervical carcinoma. E6 of the HPV-16 which expressed early in cancer cells is a target for immune therapeutic methods. In the present study, after fetching the sequence of HPV-16 E6 (accession No: ABC48950) from NCBI databank, by using hydrophilicity, flexibility, accessibility, turns, exposed surface, polarity and antigenic propensity scales, B cell epitopes of the protein were predicted. In addition, MHCPred version 2.0 program was used to predict MHC Class I and Class II alleles. The sequences of the epitopes were also found out. According to this computer-based prediction the results from A0203 and DRB0101 reveal lower IC50 than other alleles. For A0203 allele, peptide with the best binding affinity was 25ELQTTIHDI33. For DRB0101 allele, the peptide was 39YCKQQLLRR47. Different structural features of the protein were also predicted. These features were including glycosylation, kinase C phosphorylation, Casein kinase II phosphorylation and N-myristylation sites, and disulfide bonding states. By using these computational scales and programs, 0 glycosylation, 3 kinase C phosphorylation, 2 casein kinase II phosphorylation and 1 N-myristylation sites and 2 disulfide bonds were predicted. Development and approval of new vaccines are keys for control of cancer. Epitopes and structural features of proteins can be predicted and this information can help us in molecular and medical studies of viruses.
Asian Pac J Cancer Prev
PMID:Prediction of epitopes and structural properties of Iranian HPV-16 E6 by bioinformatics methods. 1826 Jul 37

In the central nervous system, the activation of neuronal nitric oxide synthase (nNOS) is closely associated with activation of NMDA receptor, and trafficking of nNOS may be a prerequisite for efficient NO production at synapses. We recently demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) and NMDA synergistically caused the translocation of nNOS to the membrane and stimulated NO production in PC12 (pheochromocytoma) cells. However, the mechanisms responsible for trafficking and activation of nNOS are largely unknown. To address these issues, here we constructed a yellow fluorescent protein (YFP)-tagged nNOS N-terminal (1-299 a.a.) mutant, nNOSNT-YFP, and visualized its translocation in PC12 cells stably expressing it. PACAP enhanced the translocation synergistically with NMDA in a time- and concentration-dependent manner. The translocation was blocked by inhibitors of protein kinase A (PKA), protein kinase C (PKC), and Src kinase; and the effect of PACAP could be replaced with PKA and PKC activators. The beta-finger region in the PSD-95/disc large/zonula occludens-1 domain of nNOS was required for the translocation of nNOS and its interaction with post-synaptic density-95 (PSD-95), and NO formation was attenuated by dominant negative nNOSNT-YFP. These results demonstrate that PACAP stimulated nNOS translocation mediated by PKA and PKC via PAC(1)-receptor (a PACAP receptor) and suggest cross-talk between PACAP and NMDA for nNOS activation by Src-dependent phosphorylation of NMDA receptors.
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PMID:Characterization of signaling pathway for the translocation of neuronal nitric oxide synthase to the plasma membrane by PACAP. 1833 76

Somatolactin (SL), the latest member of the growth hormone/prolactin family, is a novel pituitary hormone with diverse functions. However, the signal transduction mechanisms responsible for SL expression are still largely unknown. Using grass carp as an animal model, we examined the direct effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on SL gene expression at the pituitary level. In primary cultures of grass carp pituitary cells, SLalpha and SLbeta mRNA levels could be elevated by PACAP via activation of PAC-I receptors. With the use of a pharmacological approach, the AC/cAMP/PKA and PLC/inositol 1,4,5-trisphosphate (IP(3))/PKC pathways and subsequent activation of the Ca(2+)/calmodulin (CaM)/CaMK-II cascades were shown to be involved in PACAP-induced SLalpha mRNA expression. Apparently, the downstream Ca(2+)/CaM-dependent cascades were triggered by extracellular Ca(2+) ([Ca(2+)](e)) entry via L-type voltage-sensitive Ca(2+) channels (VSCC) and Ca(2+) release from IP(3)-sensitive intracellular Ca(2+) stores. In addition, the VSCC component could be activated by cAMP/PKA- and PLC/PKC-dependent mechanisms. Similar postreceptor signaling cascades were also observed for PACAP-induced SLbeta mRNA expression, except that [Ca(2+)](e) entry through VSCC, PKC coupling to PLC, and subsequent activation of CaMK-II were not involved. These findings, taken together, provide evidence for the first time that PACAP can induce SLalpha and SLbeta gene expression in fish model via PAC-I receptors through differential coupling to overlapping and yet distinct signaling pathways.
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PMID:Grass carp somatolactin: II. Pharmacological study on postreceptor signaling mechanisms for PACAP-induced somatolactin-alpha and -beta gene expression. 1852 21

In pancreatic beta-cells, the pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a potent insulin secretory effect via PAC(1) and VPAC receptors (Rs) through the Galpha(s)/cAMP/protein kinase A pathway. Here, we investigated the mechanisms linking PAC(1)R to ERK1/2 activation in INS-1E beta-cells and pancreatic islets. PACAP caused a transient (5 min) increase in ERK1/2 phosphorylation via PAC(1)Rs and promoted nuclear translocation of a fraction of cytosolic p-ERK1/2. Both protein kinase A- and Src-dependent pathways mediated this transient ERK1/2 activation. Moreover, PACAP potentiated glucose-induced long-lasting ERK1/2 activation. Blocking Ca(2+) influx abolished glucose-induced ERK1/2 activation and PACAP potentiating effect. Glucose stimulation during KCl depolarization showed that, in addition to the triggering signal (rise in cytosolic [Ca(2+)]), the amplifying pathway was also involved in glucose-induced sustained ERK1/2 activation and was required for PACAP potentiation. The finding that at 30 min glucose-induced p-ERK1/2 was detected in both cytosol and nucleus while the potentiating effect of PACAP was only observed in the cytosol, suggested the involvement of the scaffold protein beta-arrestin. Indeed, beta-arrestin 1 (beta-arr1) depletion (in beta-arr1 knockout mouse islets or in INS-1E cells by siRNA) completely abolished PACAP potentiation of long-lasting ERK1/2 activation by glucose. Finally, PACAP potentiated glucose-induced CREB transcriptional activity and IRS-2 mRNA expression mainly via the ERK1/2 signaling pathway, and likewise, beta-arr1 depletion reduced the PACAP potentiating effect on IRS-2 expression. These results establish for the first time that PACAP potentiates glucose-induced long-lasting ERK1/2 activation via a beta-arr1-dependent pathway and thus provide new insights concerning the mechanisms of PACAP and glucose actions in pancreatic beta-cells.
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PMID:beta-Arrestin 1 is required for PAC1 receptor-mediated potentiation of long-lasting ERK1/2 activation by glucose in pancreatic beta-cells. 1907 39


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