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)

Adenovirus infection of hepatoma cells inhibited transcription of the phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) gene and virtually eliminated transcription of a chimeric gene which contained the PEPCK promoter linked to the structural gene for chloramphenicol acetyltransferase (CAT). This effect is due to the viral protein E1A, since adenovirus containing a deletion in the E1A gene did not repress transcription from the PEPCK promoter. Both the 243R and 283R products of the E1A gene were effective. The conserved region 1 (CR-1) domain of E1A was required for this effect. Treatment of hepatoma cells with 8-bromo-cAMP or transfection with plasmids coding for the catalytic subunit of protein kinase A, CAAT/enhancer binding protein alpha (C/EBP), or Jun, all potent inducers of PEPCK gene transcription, did not relieve the inhibition caused by E1A. This inhibition does not appear to be mediated by major enhancer elements and in the PEPCK gene since transcription from the PEPCK promoter containing block mutations in binding domains for C/EBP and cAMP regulatory element binding protein (CREB) was also inhibited by E1A. Transcription of chimeric genes containing two copies each of the major cAMP response domains (CRE-1 and P-3) linked to a neutral promoter and fused to the CAT structural gene was stimulated by the catalytic subunit of protein kinase A, but this effect was totally inhibited by E1A. The strong repressive effect of E1A on PEPCK gene transcription seems to involve an interruption of an obligatory interaction between factors which bind to the cAMP response element in the PEPCK promoter and the TATA box.
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PMID:Adenovirus E1A represses the cyclic AMP-induced transcription of the gene for phosphoenolpyruvate carboxykinase (GTP) in hepatoma cells. 131 Mar 18

Adenovirus early region 1A (E1A) products are phosphorylated nuclear oncoproteins which appear to derive transforming activity largely through interactions with cellular proteins including the tumor suppressor p105/Rb-1 and cyclin A (p60cycA), a regulatory subunit associated with p34cdc2 and the related protein kinase p33cdk2. We have identified several sites of phosphorylation on E1A proteins previously and showed that phosphorylation at Ser-89 alters electrophoretic mobility significantly and affects E1A-mediated transforming activity to some extent. We now report that both Ser-89 and Ser-219, the major E1A phosphorylation site, were phosphorylated in vitro by p34cdc2 purified from HeLa cells. We also found that E1A proteins seemed to be phosphorylated at the highest levels in vivo in mitotic cells which express maximal levels of p34cdc2 kinase activity. Thus, in addition to forming complexes with p60cycA, a regulator of p34cdc2 and related kinases, and p105/Rb-1 which exhibits cell cycle-dependent phosphorylation, E1A proteins seem to be substrates for p34cdc2. These data suggested that a link could exist between phosphorylation, cell cycle progression, and the regulation of transforming activity of E1A proteins.
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PMID:Phosphorylation of adenovirus E1A proteins by the p34cdc2 protein kinase. 153 50

Adenovirus virus-associated (VA) RNAI maintains efficient protein synthesis during the late phase of infection by preventing the activation of the double-stranded-RNA-dependent protein kinase, DAI. A secondary structure model for VA RNAI predicts the existence of two stems joined by a complex stem-loop structure, the central domain. The structural consequences of mutations and compensating mutations introduced into the apical stem lend support to this model. In transient expression assays for VA RNA function, foreign sequences inserted into the apical stem were fully tolerated provided that the stem remained intact. Mutants in which the base of the apical stem was disrupted retained partial activity, but truncation of the apical stem abolished the ability of the RNA to block DAI activation in vitro, suggesting that the length and position of the stem are both important for VA RNA function. These results imply that VA RNAI activity depends on secondary structure at the top of the apical stem as well as in the central domain and are consistent with a two-step mechanism involving DAI interactions with both the apical stem and the central domain.
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PMID:Role of the apical stem in maintaining the structure and function of adenovirus virus-associated RNA. 154 68

The promoter motif CGTCA binds multiple cellular factors that mediate a variety of inducible events, including positive responses to raised cellular levels of cAMP and to the Adenovirus E1a protein. To date, at least ten mammalian cDNA clones have been isolated that encode distinct proteins capable of binding to this motif. However, in most cases the precise stimuli that may regulate these different factors have yet to be determined. We have previously shown that the abundant Hela protein ATF-43 forms a complex in vivo with the cyclic AMP response element binding protein (CREB). In this report we definitively show that ATF-43 is the product of the two published cDNA clones, ATF1 and TREB 36. We confirm that ATF1 efficiently heterodimerises with CREB and demonstrate that even though ATF1 and CREB homodimers, as well as the ATF1/CREB heterodimer efficiently bind to the CGTCA motif, the resulting DNA-protein complexes have significantly different stabilities. A region outside the DNA binding domain of ATF1 contributes to the instability of its interaction with DNA. We further show that despite ATF1's homology to CREB, it responds poorly to activation by protein kinase A. In light of our finding that in Hela cells the majority of CREB protein is heterodimerised with ATF1, we speculate on the functional significance of such heterodimers.
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PMID:Identification and functional characterisation of the cellular activating transcription factor 43 (ATF-43) protein. 165 49

Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.
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PMID:Adenovirus inhibition of cellular protein synthesis is prevented by the drug 2-aminopurine. 169 91

A DNA element located at positions -295 to -289 of the c-fos promoter (FAP site) is highly homologous to a consensus 12-O-tetradecanoyl phorbol-13-acetate-responsive element (TRE) and to a cyclic AMP (cAMP)-responsive element (CRE). We found that an oligonucleotide containing the FAP element was a transcription regulator which was distinct from both the TRE and CRE. When cloned in multiple copies in front of a reporter gene in HeLa cells, the FAP oligonucleotide was a powerful constitutive activator sequence. Conversely, in the same cells, reporter plasmids containing multiple copies of the TRE of the human metallothionein gene required phorbol esters for their induction. In PC12 cells, the FAP oligonucleotide was cAMP responsive. Its activity was mediated through a cAMP-dependent protein kinase II and did not rely on ongoing protein synthesis for activation. Adenovirus E1a proteins activated viral promoters through ATF (activation transcription factor) consensus binding sequences identical to the CRE. However, E1a repressed the FAP oligonucleotide-associated transcriptional activity in HeLa cells. In PC12 cells, E1a neither transactivated nor transrepressed the basal and cAMP-stimulated FAP activity. In contrast, the CRE of the human c-fos promoter located at -60 was weakly induced by cAMP and E1a in both HeLa and PC12 cells. We suggest that the FAP oligonucleotide acts through a factor(s) distinct from those employed by the TRE and CRE and that the FAP-associated protein factor(s) may differ in HeLa and PC12 cells in expression or posttranslational regulation.
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PMID:Functional analysis of an isolated fos promoter element with AP-1 site homology reveals cell type-specific transcriptional properties. 214 23

Adenovirus VA RNAL maintains protein synthesis by preventing activation of the double-stranded RNA (dsRNA)-dependent protein kinase DAI. There appears to be a single binding site for dsRNA on DAI, and this site is blocked by VA RNAl. VA RNAl binds to purified DAI and can be cross-linked to the enzyme by UV irradiation. To determine the relationship between DAI binding and VA RNAl structure and function, we examined the binding abilities of wild-type and mutant VA RNAs. In several cases, the ability to bind DAI efficiently in vitro did not correlate with function in vivo. Secondary structure analysis suggested that efficient binding requires an apical stem-loop structure, whereas inhibition of DAI activation requires the central domain of the VA RNA molecule. We propose that the duplex stem permits VA RNA to interact with the dsRNA binding site on DAI and inhibits activation by juxtaposing the central domain of the RNA with the enzyme's active site.
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PMID:Interaction of adenovirus VA RNAl with the protein kinase DAI: nonequivalence of binding and function. 218 37

Adenovirus infection induces a large increase in the DNA binding activity of a cellular transcription factor that is utilized by the viral E2 promoter and termed E2F. Using cell-free extracts, we have developed an assay for the in vitro activation of DNA binding activity of E2F. E2F activity is undetectable in HeLa extracts but upon incubation with a fraction from adenovirus-infected cells, there is an ATP-dependent increase in E2F DNA binding activity. This increase does not occur using an equivalent fraction from dl312 (E1A-)-infected cells. Incubation of E2F with phosphatase inactivates E2F binding activity. Incubation of the phosphatase-inactivated E2F with an infected cell fraction restores E2F activity as does incubation with a known protein kinase. In contrast, incubation with an extract from mock-infected cells does not restore activity. We conclude that the DNA binding activity of E2F is regulated by phosphorylation in an E1A-dependent manner.
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PMID:Phosphorylation-dependent activation of the adenovirus-inducible E2F transcription factor in a cell-free system. 252 56

Adenovirus VA RNAs (virus-associated RNAs) are small polymerase III transcripts that are required for efficient initiation of mRNA translation late in adenovirus infection. VAI RNA prevents double-stranded RNA (dsRNA) activation of the interferon-induced protein kinase (DAI kinase). Activation of this kinase results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) and correlates with inhibition of translation initiation. In this report we show growth complementation of adenoviruses harboring deletions in the VAI gene in cell lines expressing a serine-to-alanine mutant of eIF-2 alpha. This serine-to-alanine mutant is resistant to phosphorylation by DAI kinase. These results directly show that the primary function of VAI RNA in the lytic adenovirus infection is the inhibition of eIF-2 alpha phosphorylation by DAI kinase and identify eIF-2 alpha as the target that mediates the effects of DAI kinase activation. Cells that express a mutant eIF-2 alpha will enable the isolation of specific host-range mutants for other types of viruses that are defective in the ability to inhibit DAI kinase.
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PMID:Complementation of adenovirus virus-associated RNA I gene deletion by expression of a mutant eukaryotic translation initiation factor. 259 57

Adenovirus prevents host cell protein synthesis during its late phase of replication in large part by causing the underphosphorylation of translation initiation factor eIF-4E, a component of initiation factor eIF-4F (cap-binding protein complex). Late adenovirus mRNAs are preferentially translated because they possess a reduced requirement for eIF-4F. This study continues the characterization of the mechanism by which adenovirus inhibits cellular protein synthesis. First it is shown that adenovirus blocks the addition of phosphate to eIF-4E rather than enhancing its removal, establishing that the virus impairs a signalling pathway or protein kinase activity involved in eIF-4E phosphorylation. It is then shown that shutoff of cell protein synthesis and translation of late viral mRNAs are uncoupled, in that shutoff actually occurs a short time (1 to 3 h) after late adenovirus mRNAs are already undergoing translation. Finally, by using a variety of genetic mutants stalled at different stages in the viral life cycle, it was found that dephosphorylation of eIF-4E and inhibition of cell translation are not caused by early adenovirus gene products acting at late times or by events related to viral DNA replication. Instead, it is shown that inhibition of eIF-4E phosphorylation and cell translation are mediated upon activation of the viral major late transcription unit. These and other results presented indicate that the adenovirus signal which induces eIF-4E dephosphorylation and shutoff of cell protein synthesis is linked either to an activity of one or more late viral polypeptides, to double-stranded RNA produced by opposition of the early and late viral transcription units, or to both.
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PMID:A late adenovirus factor induces eIF-4E dephosphorylation and inhibition of cell protein synthesis. 793 86


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