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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinases (CDKs) that control cell cycle progression are regulated in many ways, including activating phosphorylation of a conserved threonine residue. This essential phosphorylation is carried out by the CDK-activating kinase (CAK). Here we examine the effects of replacing this threonine residue in human CDK2 by serine. We found that cyclin A bound equally well to wild-type CDK2 (CDK2(Thr-160)) or to the mutant CDK2 (CDK2(Ser-160)). In the absence of activating phosphorylation, CDK2(Ser-160)-cyclin A complexes were more active than wild-type CDK2(Thr-160)-cyclin A complexes. In contrast, following activating phosphorylation, CDK2(Ser-160)-cyclin A complexes were less active than phosphorylated CDK2(Thr-160)-cyclin A complexes, reflecting a much smaller effect of activating phosphorylation on CDK2(Ser-160). The kinetic parameters for phosphorylating histone H1 were similar for mutant and wild-type CDK2, ruling out a general defect in catalytic activity. Interestingly, the CDK2(Ser-160) mutant was selectively defective in phosphorylating a peptide derived from the C-terminal domain of RNA polymerase II. CDK2(Ser-160) was efficiently phosphorylated by CAKs, both human p40(MO15)(CDK7)-cyclin H and budding yeast Cak1p. In fact, the k(cat) values for phosphorylation of CDK2(Ser-160) were significantly higher than for phosphorylation of CDK2(Thr-160), indicating that CDK2(Ser-160) is actually phosphorylated more efficiently than wild-type CDK2. In contrast, dephosphorylation proceeded more slowly with CDK2(Ser-160) than with wild-type CDK2, either in HeLa cell extract or by purified PP2Cbeta. Combined with the more efficient phosphorylation of CDK2(Ser-160) by CAK, we suggest that one reason for the conservation of threonine as the site of activating phosphorylation may be to favor unphosphorylated CDKs following the degradation of cyclins.
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PMID:The effects of changing the site of activating phosphorylation in CDK2 from threonine to serine. 1093 29

One class of heterogeneous nuclear ribonucleoproteins (hnRNPs), AUF1/hnRNP D, consists of four isoform proteins (p45, p42, p40, and p37) which are generated by alternative splicing. The present study was therefore undertaken to clarify any isoform-specific differences in terms of their functions and nucleocytoplasmic localization. All isoforms primarily localized in the nucleus. However, heterokaryon analysis and a study using RNA polymerase II inhibitor revealed that p40/p37 exhibited a continuous shuttling between the nucleus and cytoplasm. Constant nuclear retention activity was mapped to the p45/p42-specific sequence at the C-terminal region, which is retained by alternative splicing. Using this domain as a probe, we performed a yeast two-hybrid screening and we found that scaffold attachment factor B (SAF-B), a nuclear matrix-associated protein, exhibits protein-protein interaction to this region. Colocalization of p45/p42 and SAF-B was observed as a speckle in the nucleus. Interestingly, p45/p42 isoforms appeared to act as a negative regulator in gene expression by forming a complex with SAF-B. Thus, the present study revealed that the isoform-specific functions of AUF1/hnRNP D are defined by intracellular shuttling capacity.
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PMID:A nuclear matrix-associated factor, SAF-B, interacts with specific isoforms of AUF1/hnRNP D. 1093 76

Borna disease virus (BDV) has been suggested to play a role in the etiology of schizophrenia. We tested the hypothesis that markers of BDV infection are more frequent in Surinamese immigrants to the Netherlands, diagnosed with schizophrenia, than in Dutch-born healthy subjects. For reasons that are poorly understood there is an increased incidence of schizophrenia in this immigrant group. Blood was obtained from 29 male schizophrenic patients (DSM-IV criteria) and from 26 healthy males. For detection of anti-BDV antibodies an indirect immunofluorescence assay (IFA) was performed. A nested, reverse-transcriptase-PCR, using primers specific for the p24 and p40 BDV genes, was used to determine BDV-RNA in peripheral blood mononuclear cells. Contrary to our expectations, the frequencies of BDV markers in the group of healthy subjects, as determined by IFA and both PCRs, exceeded that in the group of patients. The results do not support an association between markers of BDV infection in blood and schizophrenia. It is unlikely that the high incidence of schizophrenia in Surinamese immigrants is caused by BDV, but the small number of subjects examined do not warrant definitive conclusions.
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PMID:Borna disease virus and schizophrenia in Surinamese immigrants to the Netherlands. 1113 37

The GAGA box of the rat serine protease inhibitor 2 (spi 2) genes not only acts as a basal promoter element, but also mediates transcriptional activation by growth hormone and interleukin-6. The GAGA box is separated from the TATA box by only 12 bp, and this close association is required for efficient transcription. Hence, the GAGA box may influence transcription efficiency through interactions between GAGA box binding proteins and some components of the RNA polymerase II complex. Here we report the cloning of two GAGA box-binding proteins termed p38 and p40, that belong to the type A/B heterogeneous nuclear ribonucleoprotein subgroup. GAGA box mutations that diminish the affinity for p38 and p40 decrease basal and GH-induced reporter gene expression. Furthermore, nuclear extracts depleted of p38 and p40 can no longer support GAGA box-dependent in vitro transcription. Therefore, two polypeptides previously assigned to a family of RNA processing proteins also act as DNA-binding, promoter-specific transcription factors.
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PMID:Purification and cloning of type A/B hnRNP proteins involved in transcriptional activation from the Rat spi 2 gene GAGA box. 1115 60

In light of the important role of cytokines in the pathogenesis of bacterial infections, we analyzed the cytokine production induced by different Staphylococcus aureus (S. aureus), S. epidermidis and S. saprophyticus strains in human mononuclear cells (MNCs). MNCs secreted high amounts of interleukin-1beta (IL-1beta) and IL-6 proteins in responses to stimulation with all three species of Staphylococci. Interestingly, a large majority of the S. aureus strains induced significantly higher IL-12 and interferon (IFN) titers than did the S. epidermidis and S. saprophyticus strains. The RNase protection assay revealed high increases in IL-1alpha, IL-1 beta, IL-1 receptor antagonist, IL-6 and IL-12 p40 transcript levels in MNCs stimulated with Staphylococci. All of the tested Staphylococcal strains proved highly efficient in mediating the induction of these genes. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis indicated considerable increases in IFNA transcript levels in MNCs stimulated with S. aureus strains, while only a very weak expression was stimulated by S. epidermidis and S. saprophyticus. These results confirm that heat-killed Staphylococci exert strong immunomodulatory effects, and suggest that the contribution of T-helper 1 (Th(1)) cells to the immune response may be much extensive in infections caused by S. aureus strains, due to their high IL-12p70 and IFN-alpha-inducing activities.
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PMID:Induction of cytokine production by different Staphylococcal strains. 1229 15

Activation of cyclin-dependent kinases (CDKs) requires phosphorylation of a threonine residue within the T-loop by a CDK-activating kinase (CAK). Here we isolated an Arabidopsis cDNA (CAK4At) whose predicted product shows a high similarity to vertebrate CDK7/p40(MO15). Northern blot analysis showed that expressions of the four Arabidopsis CAKs (CAK1At-CAK4At) were not dependent on cell division. CAK2At- and CAK4At-immunoprecipitates of Arabidopsis crude extract phosphorylated CDK and the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II with different preferences. These results suggest the existence of differential mechanisms in Arabidopsis that control CDK and CTD phosphorylation by multiple CAKs.
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PMID:Differential phosphorylation activities of CDK-activating kinases in Arabidopsis thaliana. 1252 63

Interleukin-10 (IL-10) is a potent anti-inflammatory cytokine that suppresses the induction of proinflammatory cytokine genes, including the IL-12 p40 gene. Despite considerable effort examining the effect of IL-10 on specific transcription factors and signaling molecules, the mechanism by which IL-10 inhibits gene transcription has remained elusive. To provide a different perspective to this problem, we examined the effect of IL-10 on molecular events occurring at the endogenous IL-12 p40 locus in lipopolysaccharide-stimulated peritoneal macrophages. IL-10 abolished recruitment of RNA polymerase II to the p40 promoter. However, it only modestly reduced binding of C/EBPbeta, as monitored by genomic footprinting and chromatin immunoprecipitation. It also had little effect on NF-kappaB complexes that are critical for p40 induction. A substantial reduction in nucleosome remodeling at the p40 promoter was observed, but the magnitude of this reduction appeared insufficient to account for the strong inhibition of transcription. Finally, a lipopolysaccharide-inducible DNase I hypersensitive site identified 10 kb upstream of the start site was unaffected by IL-10. Thus, despite a dramatic reduction in p40 transcription, several events required for activation of the endogenous p40 gene occurred relatively normally. These findings suggest that IL-10 blocks one or more events that occur after p40 locus decondensation and nucleosome remodeling and after, or in parallel with, the binding of a subset of p40 transcriptional activators.
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PMID:Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway. 1499 78

We evaluated the effect of interleukin-12 (IL-12) gene therapy using an Ewing's sarcoma animal model in T-cell-deficient nude mice. Subcutaneous injection of TC71 cells resulted in tumor development by day 5. Mice were treated with a single intratumor injection of adenovirus beta-galactosidase (Ad.beta-gal) or adenovirus murine IL-12 (Ad.mIL-12) (2 x 10(9) PFU) and killed 1-7 days later. Reverse transcriptase-polymerase chain reaction analysis of tumor tissue demonstrated peak expression of IL-12 p35 and p40 at 48 h, which persisted up to 7 days. For in vivo therapy, mice received intratumor Ad.beta-gal or Ad.mIL-12 twice weekly for 2.5 weeks starting on day 6. Ad.mIL-12-treated tumors were significantly smaller (median volume, 19.7 mm3; range, 3.41-159.5 mm3) than Ad.beta-gal-treated tumors (median volume, 3214.9 mm3; range 1679.9-5909.8 mm3, P<0.003) on day 31. The weight of Ad.mIL-12-treated tumors was also lighter than the Ad.beta-gal-treated tumors (median, 2 mg; range, 1-5 mg versus median, 1960 mg; range 1640-5230 mg, P<0.01). Ad.mIL-12 therapy significantly prolonged the survival time and also inhibited the growth of an untreated tumor on the contralateral side. Immunohistochemistry analysis of the IL-12-treated tumors demonstrated IL-12 expression with increased Fas, Fas ligand and tumor cell apoptosis. CD31 and vascular endothelial growth factor expression were decreased. These data suggest that IL-12 gene therapy may be useful in the treatment of Ewing's sarcoma.
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PMID:Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma. 1676 9

The aims of the present study were to investigate the expression of Toll-like receptor (TLR)2 on the peripheral blood monocytes of patients with nontuberculous mycobacterial (NTM) lung disease and healthy controls, and to assess the responses of these monocytes to TLR2 agonists such as Mycobacterium avium and lipoteichoic acid (LTA). Reverse transcriptase-PCR was used to analyse TLR2 mRNA expression in peripheral blood monocytes from 17 NTM patients and 10 healthy controls. mRNA and protein secretion levels were also determined for the cytokines interleukin (IL)-12 p40 and tumour necrosis factor (TNF)-alpha. Expression of TLR2 mRNA by peripheral blood monocytes after stimulation with M. avium or LTA was lower in NTM patients than in healthy controls. IL-12 p40 and TNF-alpha mRNA and cytokine secretion levels were also lower in patients than in healthy controls. Treatment with anti-TLR antibody decreased M. avium- and LTA-induced IL-12 p40 and TNF-alpha production in healthy controls, but not in NTM patients. The present results suggest that the downregulation of Toll-like receptor 2 and the resulting decreased production of interleukin-12 p40 and tumour necrosis factor-alpha following Mycobacterium avium or lipoteichoic acid stimulation may contribute to host susceptibility to nontuberculous mycobacterial lung disease.
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PMID:Impaired expression of Toll-like receptor 2 in nontuberculous mycobacterial lung disease. 1756 74

SKIN(2) ZK1300 is a three-dimensional human skin model consisting of multilayered dermal fibroblasts and well-differentiated epidermal keratinocyte layers, including a stratum corneum. To characterize this model better, constitutive levels of cytokine gene expression were determined. Reverse transcriptase-polymerase chain reaction (RT-PCR), followed by liquid hybridization to labelled internal probes, demonstrated that interleukin (IL)-1I, IL-1beta, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)I, granulocyte macrophage-colony stimulating factor (GM-CSF), transforming growth factor (TGFbeta1) and IL-12 p35 mRNAs were constitutively expressed whereas IL-12 p40 was not. The contribution of the dermal component of this human skin model (Model ZK1100) was further characterized by determining constitutive cytokines expressed and their modulation by phorbol 12-myristate, 13-acetate (PMA). The dermal component, consisting of multilayered human dermal fibroblasts, constitutively expressed message for IL-1I, 1L-1beta, IL-6, IL-8, TGFbeta1, GM-CSF and IL-12 p35. Message was not detected for IL-10, TNFI or IL-12 p40. PMA treatment of the multilayered dermal fibroblasts increased steady-state mRNA levels of IL-1I, IL-1beta, IL-6, IL-8, GM-CSF and TGFbeta1, but did not induce IL-10, TNFI or IL-12 p40 expression at the dose and times tested. In summary, these studies demonstrate that the SKIN(2) three-dimensional human skin cultures, and their dermal component, constitutively express mRNA for an array of inflammatory and immunomodulatory cytokines, and that PMA exposure modulates mRNA levels of the dermal cytokines.
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PMID:Cytokine mRNA expression in an in vitro human skin model, SKIN(2). 2065 Feb 32


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