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)

Death-associated protein kinase is a positive regulator of programmed cell death induced by interferon gamma. To investigate the role of epigenetic inactivation of death-associated protein kinase in gastrointestinal cancer, we examined the methylation status of the 5' CpG island of the death-associated protein kinase gene. Methylation of the 5' CpG island was detected in 3 of 9 colorectal and 3 of 17 gastric cancer cell lines, while among primary tumours, it was detected in 4 of 28 (14%) colorectal and 4 of 27 (15%) gastric cancers. By contrast, methylation of the edge of the CpG island was detected in virtually every sample examined. Death-associated protein kinase expression was diminished in four cell lines that showed dense methylation of the 5' CpG island, and treatment with 5-aza-2'-deoxycitidine, a methyltransferase inhibitor, restored gene expression. Acetylation of histones H3 and H4 in the 5' region of the gene was assessed by chromatin immunoprecipitation and was found to correlate directly with gene expression and inversely with DNA methylation. Thus, aberrant DNA methylation and histone deacetylation of the 5' CpG island, but not the edge of the CpG island, appears to play a key role in silencing death-associated protein kinase expression in gastrointestinal malignancies.
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PMID:DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers. 1208 72

A substrate for protein kinase B (PKB)alpha in HeLa cell extracts was identified as methyltransferase-like protein-1 (METTL1), the orthologue of trm8, which catalyses the 7-methylguanosine modification of tRNA in Saccharomyces cerevisiae. PKB and ribosomal S6 kinase (RSK) both phosphorylated METTL1 at Ser27 in vitro. Ser27 became phosphorylated when HEK293 cells were stimulated with insulin-like growth factor-1 (IGF-1) and this was prevented by inhibition of phosphatidyinositol 3-kinase. The IGF-1-induced Ser27 phosphorylation did not occur in 3-phosphoinositide-dependent protein kinase-1 (PDK1)-deficient embryonic stem cells, but occurred normally in PDK1[L155E] cells, indicating that the effect of IGF-1 is mediated by PKB. METTL1 also became phosphorylated at Ser27 in response to phorbol-12-myristate 13-acetate and this was prevented by PD 184352 or pharmacological inhibition of RSK. Phosphorylation of METTL1 by PKB or RSK inactivated METTL1 in vitro, as did mutation of Ser27 to Asp or Glu. Expression of METTL1[S27D] or METTL1[S27E] did not rescue the growth phenotype of yeast lacking trm8. In contrast, expression of METTL1 or METTL1[S27A] partially rescued growth. These results demonstrate that METTL1 is inactivated by PKB and RSK in cells, and the potential implications of this finding are discussed.
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PMID:The tRNA methylase METTL1 is phosphorylated and inactivated by PKB and RSK in vitro and in cells. 1586 Nov 36

Farnesoic acid O-methyltransferase (FaMeT) is the enzyme responsible for the conversion of farnesoic acid (FA) to methyl farnesoate (MF) in the final step of MF synthesis. Multiple isoforms of putative FaMeT were isolated from six crustacean species belonging to the families Portunidae, Penaeidae, Scyllaridae and Parastacidae. The portunid crabs Portunus pelagicus and Scylla serrata code for three forms: short, intermediate and long. Two isoforms (short and long) were isolated from the penaeid prawns Penaeus monodon and Fenneropenaeus merguiensis. Two isoforms were also identified in the scyllarid Thenus orientalis and parastacid Cherax quadricarinatus. Putative FaMeT sequences were also amplified from the genomic DNA of P. pelagicus and compared to the putative FaMeT transcripts expressed. Each putative FaMeT cDNA isoform was represented in the genomic DNA, indicative of a multi-gene family. Various tissues from P. pelagicus were individually screened for putative FaMeT expression using PCR and fragment analysis. Each tissue type expressed all three isoforms of putative FaMeT irrespective of sex or moult stage. Protein domain analysis revealed the presence of a deduced casein kinase II phosphorylation site present only in the long isoform of putative FaMeT.
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PMID:Isolation and expression analysis of multiple isoforms of putative farnesoic acid O-methyltransferase in several crustacean species. 1699 57

We isolated several senescence-associated genes (SAGs) from the petals of morning glory (Ipomoea nil) flowers, with the aim of furthering our understanding of programmed cell death. Samples were taken from the closed bud stage to advanced visible senescence. Actinomycin D, an inhibitor of transcription, if given prior to 4 h after opening, suppressed the onset of visible senescence, which occurred at about 9 h after flower opening. The isolated genes all showed upregulation. Two cell-wall related genes were upregulated early, one encoding an extensin and one a caffeoyl-CoA-3-O-methyltransferase, involved in lignin production. A pectinacetylesterase was upregulated after flower opening and might be involved in cell-wall degradation. Some identified genes showed high homology with published SAGs possibly involved in remobilisation processes: an alcohol dehydrogenase and three cysteine proteases. One transcript encoded a leucine-rich repeat receptor protein kinase, putatively involved in signal transduction. Another transcript encoded a 14-3-3 protein, also a protein kinase. Two genes have apparently not been associated previously with senescence: the first encoded a putative SEC14, which is required for Golgi vesicle transport, the second was a putative ataxin-2, which has been related to RNA metabolism. Induction of the latter has been shown to result in cell death in yeast, due to defects in actin filament formation. The possible roles of these genes in programmed cell death are discussed.
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PMID:Gene expression in opening and senescing petals of morning glory (Ipomoea nil) flowers. 1722 Dec 29

Mog1 is conserved from yeast to mammal, but its function is obscure. We isolated yeast genes that rescued a temperature-sensitive death of S. cerevisiae Scmog1Delta, and of S. pombe Spmog1(ts). Scmog1Delta was rescued by Opi3p, a phospholipid N-methyltransferase, in addition to S. cerevisiae Ran-homologue Gsp1p, and a RanGDP binding protein Ntf2p. On the other hand, Spmog1(ts) was rescued by Cid13 that is a poly (A) polymerase specific for suc22(+) mRNA encoding a subunit of ribonucleotide reductase, Ssp1 that is a protein kinase involved in stress response pathway, and Crp79 that is required for mRNA export, in addition to Spi1, S. pombe Ran-homologue, and Nxt2, S. pombe homologue of Ntf2p. Consistent with the identification of those suppressors, lack of ScMog1p dislocates Opi3p from the nuclear membrane and all of Spmog1(ts) showed the nuclear accumulation of mRNA. Furthermore, SpMog1 was co-precipitated with Nxt2 and Cid13.
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PMID:Identification of novel suppressors for Mog1 implies its involvement in RNA metabolism, lipid metabolism and signal transduction. 1765 22

l-Aspartyl (l-Asp) and l-asparaginyl residues in proteins isomerize or racemize to d,l-isoaspartyl (d,l-isoAsp) or d-aspartyl (d-Asp) residues during protein aging. These atypical aspartyl residues can interfere with the biological function of the protein and lead to cellular dysfunction. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a repair enzyme that facilitates conversion of l-isoAsp and d-Asp to l-Asp. PIMT deficient mice exhibit accumulation of l-isoAsp in several tissues and die, on average, 12 days after birth from progressive epileptic seizures with grand mal and myoclonus features. However, little is known about the molecular mechanisms by which accumulation of the aberrant residues leads to cellular abnormalities. In this study, we established PIMT-knockdown cells using a short interfering RNA expression system and characterized the resultant molecular abnormalities in intracellular signaling pathways. PIMT-knockdown cells showed significant accumulation of proteins with isomerized residues, compared to control cells. In the PIMT-knockdown cells, Raf-1, MEK, and ERK, members of the MAPK cascade, were hyperphosphorylated after EGF stimulation compared to control cells. These results suggest that PIMT repair of abnormal proteins is necessary to maintain normal MAPK signaling.
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PMID:Suppression of protein l-isoaspartyl (d-aspartyl) methyltransferase results in hyperactivation of EGF-stimulated MEK-ERK signaling in cultured mammalian cells. 1838 Dec

The Saccharomyces cerevisiae protein Hsl7 is a regulator of the Swe1 protein kinase in cell cycle checkpoint control. Hsl7 has been previously described as a type III protein arginine methyltransferase, catalyzing the formation of omega-monomethylarginine residues on non-physiological substrates. However, we show here that Hsl7 can also display type II activity, generating symmetric dimethylarginine residues on calf thymus histone H2A. Symmetric dimethylation is only observed when enzyme and the methyl-accepting substrate were incubated for extended times. We confirmed the Hsl7-dependent formation of symmetric dimethylarginine by amino acid analysis and thin layer chromatography with wild-type and mutant recombinant enzymes expressed from both bacteria and yeast. This result is significant because no type II activity has been previously demonstrated in S. cerevisiae. We also show that Hsl7 has little or no activity on GST-GAR, a commonly used substrate for protein arginine methyltransferases, and only minimal activity on myelin basic protein. This enzyme thus may only recognize only a small subset of potential substrate proteins in yeast, in contrast to the situation with Rmt1, the major type I methyltransferase.
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PMID:Hsl7 is a substrate-specific type II protein arginine methyltransferase in yeast. 1851 76

During cell aging, proteins accumulate damages, which affect their structure and activity. The protein l-isoaspartyl methyltransferase (PIMT) is involved in the repair of proteins containing abnormal L-isoaspartyl residues. Although its mechanism of action is well defined, little is known about the pathways involved in the regulation of PIMT expression. In this study, we demonstrated that glycogen synthase kinase-3 (GSK-3) and beta-catenin are involved in the regulation of PIMT expression. Treatment of astrocytoma cells (U-87) with direct pharmacological GSK-3 inhibitors such as lithium, SB-216763 and SB-415286 stimulated PIMT expression ( approximately twofold). As expected, GSK-3 inhibition led to an increase of phosphorylated GSK-3beta (Ser9) and to beta-catenin accumulation. PIMT induction by lithium was dependent on increased protein synthesis. In addition, RT-PCR analysis showed higher level of PIMT mRNA following GSK-3 inhibition, which was abolished by the transcriptional inhibitor actinomycin D. These results demonstrated regulation of PIMT expression by lithium at both the transcriptional and the translational levels. Additionally, inhibition by siRNA of GSK-3 and beta-catenin modulated the expression of the PIMT in accordance with GSK-3 pharmacological inhibition. Valproic acid, an antiepileptic drug with mood-stabilizing properties, up-regulated phospho-GSK-3beta (Ser9), beta-catenin and PIMT levels similarly to lithium. This study reports that PIMT expression is up-regulated by GSK-3 inhibition and beta-catenin stabilization upon treatments with lithium and valproic acid. These findings suggest a possible therapeutic role for PIMT in certain brain diseases including epilepsy.
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PMID:Up-regulation of protein L-isoaspartyl methyltransferase expression by lithium is mediated by glycogen synthase kinase-3 inactivation and beta-catenin stabilization. 1858 78

In the present study, the molecular karyotypes of 12 KP1(+) and KP1(-) Trypanosoma rangeli strains were determined and 10 different molecular markers were hybridized to the chromosomes of the parasite, including seven obtained from T. rangeli [ubiquitin hydrolase (UH), a predicted serine/threonine protein kinase (STK), hexose transporter, hypothetical protein, three anonymous sequences] and three from Trypanosoma cruzi [ubiquitin-conjugating enzyme E2 (UBE2), ribosomal RNA methyltransferase (rRNAmtr), proteasome non-ATPase regulatory subunit 6 (PSMD6)]. Despite intraspecific variation, analysis of the karyotype profiles permitted the division of the T. rangeli strains into two groups coinciding with the KP1(+) and KP1(-) genotypes. Southern blot hybridization showed that, except for the hexose transporter probe, all other probes produced distinct patterns able to differentiate the KP1(+) and KP1(-) genotypes. The UH, STK and An-1A04 probes exclusively hybridized to the chromosomes of KP1(+) strains and can be used as markers of this group. In addition, the UBE2, rRNAmtr and PSMD6 markers, which are present in a conserved region in all trypanosomatid species sequenced so far, co-hybridized to the same T. rangeli chromosomal bands, suggesting the occurrence of gene synteny in these species. The finding of distinct molecular karyotypes in KP1(+) and KP1(-) strains of T. rangeli is noteworthy and might be used as a new approach to the study of genetic variability in this parasite. Together with the Southern blot hybridization results, these findings demonstrate that differences at the kDNA level might be associated with variations in nuclear DNA.
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PMID:Karyotype variability in KP1(+) and KP1(-) strains of Trypanosoma rangeli isolated in Brazil and Colombia. 1928 97

3-Deazaadenosine (c3Ado) is a potent inhibitor of S-adenosylhomocysteine hydrolase, which regulates cellular methyltransferase activity. In the present study, we sought to determine the effect of c3Ado on vascular smooth muscle cell (VSMC) function and neointima formation in vivo. c3Ado dose-dependently prevented the proliferation and migration of human coronary VSMCs in vitro. This was accompanied by an increased expression of the cyclin-dependent kinase inhibitors p21(WAF1/Cip1), p27(Kip1), a decreased expression of G(1)/S phase cyclins, and a lack of retinoblastoma protein hyperphosphorylation. In accordance with these findings, fluorescence-activated cell-sorting analysis of propidium iodide-stained cells indicated a cell cycle arrest in the G(0)/G(1) phase. Importantly, c3Ado did not affect the number of viable (trypan blue exclusion) or apoptotic cells (TUNEL). Mechanistically, c3Ado prevented FCS-induced Ras carboxyl methylation and membrane translocation and activity by inhibiting isoprenylcysteine carboxyl methyltransferase and reduced FCS-induced extracellular signal-regulated kinase (ERK)1/2 and Akt phosphorylation in a dose-dependent manner. Conversely, rescuing signal transduction by overexpression of a constitutive active Ras mutant abrogated c3Ado's effect on proliferation. For in vivo studies, the femoral artery of C57BL/6 mice was dilated and mice were fed a diet containing 150 microg of c3Ado per day. c3Ado prevented dilation-induced Ras activation, as well as ERK1/2 and Akt phosphorylation in vivo. At day 21, VSMC proliferation (proliferating-cell nuclear antigen [PCNA]-positive cells), as well as the neointima/media ratio (0.7+/-0.2 versus 1.6+/-0.4; P<0.05) were significantly reduced, without any changes in the number of apoptotic cells. Our data indicate that c3Ado interferes with Ras methylation and function and thereby with mitogenic activation of ERK1/2 and Akt, preventing VSMC cell cycle entry and proliferation and neointima formation in vivo. Thus, therapeutic inhibition of S-adenosylhomocysteine hydrolase by c3Ado may represent a save and effective novel approach to prevent vascular proliferative disease.
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PMID:3-Deazaadenosine prevents smooth muscle cell proliferation and neointima formation by interfering with Ras signaling. 1946 Nov 5


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