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

---

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

FK506, an immunosuppressant drug used to prevent allograft rejection in organ transplantations, accelerates functional recovery and nerve regeneration in the rat sciatic nerve crush model. While the mechanism by which FK506 increases regeneration is unknown, in contrast to immunosuppression, it does not involve calcineurin inhibition. Using the reverse-transcriptase polymerase chain reaction (RT-PCR) technique and a digoxigenin-labeled probe, we show that subcutaneous injections of FK506 (10 mg/kg/day) markedly increases the level of axotomy-induced growth-associated protein (GAP-43) mRNA in dorsal root ganglion (DRG) neurons. Quantitation of DRG neurons revealed that FK506 produced a 33% increase in the numbers of neurons exhibiting intense staining. Increased synthesis of GAP-43 may play a role in FK506's ability to speed nerve regeneration.
...
PMID:The immunosuppressant FK506 increases GAP-43 mRNA levels in axotomized sensory neurons. 950 7

We have identified two Saccharomyces cerevisiae genes that, in high copy, confer resistance to Kluyveromyces lactis zymocin, an inhibitor that blocks cells in the G(1) phase of the cell cycle prior to budding and DNA replication. One gene (GRX3) encodes a glutaredoxin and is likely to act at the level of zymocin entry into sensitive cells, while the other encodes Sap155p, one of a family of four related proteins that function positively and interdependently with the Sit4p protein phosphatase. Increased SAP155 dosage protects cells by influencing the sensitivity of the intracellular target and is unique among the four SAP genes in conferring zymocin resistance in high copy, but is antagonized by high-copy SAP185 or SAP190. Since cells lacking SIT4 or deleted for both SAP185 and SAP190 are also zymocin resistant, our data support a model whereby high-copy SAP155 promotes resistance by competition with the endogenous levels of SAP185 and SAP190 expression. Zymocin sensitivity therefore requires a Sap185p/Sap190p-dependent function of Sit4p protein phosphatase. Mutations affecting the RNA polymerase II Elongator complex also confer K. lactis zymocin resistance. Since sit4Delta and SAP-deficient strains share in common several other phenotypes associated with Elongator mutants, Elongator function may be a Sit4p-dependent process.
...
PMID:Sit4p protein phosphatase is required for sensitivity of Saccharomyces cerevisiae to Kluyveromyces lactis zymocin. 1177 90

HIV-1 Tat protein regulates viral gene expression by modulating the activity and association of cellular transcription factors with RNA polymerase II (RNAPII). Possible mechanisms include Tat-associated protein kinase(s) and phosphatase(s) that regulate phosphorylation of the C-terminal domain (CTD) of the large subunit of RNAPII. Hypophosphorylated RNAPII (RNAPIIa) is recruited to promoters during formation of a preinitiation complex, whereas hyperphosphorylated RNAPII (RNAPIIo) is associated with the elongation complex. The role of phosphatases in maintaining the equilibrium between the two phosphorylated states of RNAPII, which is required for sustained transcriptional activation from the HIV-1 LTR, is not clear. In this study, we discuss the properties of a Tat-associated CTD phosphatase fractionated from Jurkat T cells. The Tat-associated protein phosphatase (TAPP) is related to the serine/threonine, type 1, protein phosphatase (PP1) family. TAPP dephosphorylates the hyperphosphorylated form of recombinant CTD specifically on serine 2, and augments Tat-mediated transcriptional transactivation of HIV-1 LTR in an in vitro transcription reaction. TAPP is associated with the transcription complex during the early initiation steps, and its release from the HIV-1 promoter coincides with the Tat-specific activation of CDK9. The results suggest a unique role of the Tat-associated phosphatase which regulates viral transcription by target-specific dephosphorylation of RNAPII during the early stages of elongation.
...
PMID:A protein phosphatase from human T cells augments tat transactivation of the human immunodeficiency virus type 1 long-terminal repeat. 1203 13

Stimulation of transcriptional elongation by the human immunodeficiency virus type 1 Tat protein is mediated by CDK9, a kinase that phosphorylates the RNA polymerase II carboxyl-terminal domain (CTD). In order to obtain direct evidence that this phosphorylation event can alter RNA polymerase processivity, we prepared transcription elongation complexes that were arrested by the lac repressor. The CTD was then dephosphorylated by treatment with protein phosphatase 1. The dephosphorylated transcription complexes were able to resume the transcription elongation when IPTG (isopropyl-beta-D-thiogalactopyranoside) and nucleotides were added to the reaction. Under these chase conditions, efficient rephosphorylation of the CTD was observed in complexes containing the Tat protein but not in transcription complexes prepared in the absence of Tat protein. Immunoblots and kinase assays with synthetic peptides showed that Tat activated CDK9 directly since the enzyme and its cyclin partner, cyclin T1, were present at equivalent levels in transcription complexes prepared in the presence or absence of Tat. Chase experiments with the dephosphorylated elongation transcription complexes were performed in the presence of the CDK9 kinase inhibitor DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole). Under these conditions there was no rephosphorylation of the CTD during elongation, and transcription through either a stem-loop terminator or bent DNA arrest sequence was strongly inhibited. In experiments in which the CTD was phosphorylated prior to elongation, the amount of readthrough of the terminator sequences was proportional to the extent of the CTD modification. The change in processivity is due to CTD phosphorylation alone, since even after the removal of Spt5, the second substrate for CDK9, RNA polymerase elongation is enhanced by Tat-activated CDK9 activity. We conclude that phosphorylation of the RNA polymerase II CTD by CDK9 enhances transcription elongation directly.
...
PMID:Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. 1205 71

Transcription by RNA polymerase-II (RNAPII) is controlled by multisite phosphorylation of the heptapeptide repeats in the C-terminal domain (CTD) of the largest subunit. Phosphorylation of CTD is mediated by the cyclin-dependent protein kinases Cdk7 and Cdk9, whereas protein serine/threonine phosphatase FCP1 dephosphorylates CTD. We have recently reported that human immunodeficiency virus-1 (HIV-1) transcription is positively regulated by protein phosphatase-1 (PP1) and that PP1 dephosphorylates recombinant CTD. Here, we provide further evidence that PP1 can dephosphorylate RNAPII CTD. In vitro, PP1 dephosphorylated recombinant CTD as well as purified RNAPII CTD. HeLa nuclear extracts were found to contain a species of PP1 that dephosphorylates both serine 2 and serine 5 of the heptapeptide repeats. In nuclear extracts, PP1 and FCP1 contributed roughly equally to the dephosphorylation of serine 2. PP1 co-purified with RNAPII by gel filtration and associated with RNAPII on immunoaffinity columns prepared with anti-CTD antibodies. In cultured cells treated with CTD kinase inhibitors, the dephosphorylation of RNAPII on serine 2 was inhibited by 45% by preincubation with okadaic acid, which inhibits phosphatases of PPP family, including PP1 but not FCP1. Our data demonstrate that RNAPII CTD is dephosphorylated by PP1 in vitro and by PPP-type phosphatase, distinct from FCP1, in vivo.
...
PMID:Protein phosphatase-1 dephosphorylates the C-terminal domain of RNA polymerase-II. 1218 79

The synthesis of mRNA by RNA polymerase II (RNAPII) is a multistep process that is regulated by different mechanisms. One important aspect of transcriptional regulation is phosphorylation of components of the transcription apparatus. The phosphorylation state of RNAPII carboxy-terminal domain (CTD) is controlled by a variety of protein kinases and at least one protein phosphatase. We discuss emerging genetic and biochemical evidence that points to a role of these factors not only in transcription initiation but also in elongation and possibly termination. In addition, we review phosphorylation events involving some of the general transcription factors (GTFs) and other regulatory proteins. As an interesting example, we describe the modulation of transcription associated kinases and phosphatase by the HIV Tat protein. We focus on bringing together recent findings and propose a revised model for the RNAPII phosphorylation cycle.
...
PMID:Regulation of transcription elongation by phosphorylation. 1221 57

Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.
...
PMID:Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. 1236 4

A subset of cyclin-dependent protein kinases--Cdk7, Cdk8, and Cdk9--participates directly, in complex ways, with the fundamental machinery for gene transcription, as elements of general transcription factors whose substrate is the C-terminal domain (CTD) of RNA polymerase II. Here, we review recent data implicating the CTD kinase Cdk9 as a critical determinant of cardiac hypertrophy, in vitro and in vivo. Diverse trophic signals that increase cardiac mass all activated Cdk9 (work load, the small G-protein Gaq, and the calcium-dependent phosphatase calcineurin in mouse myocardium; endothelin-1, a hypertrophic agonist, in cultured cardiomyocytes). Little or no change occurred in levels of the kinase or its activator, cyclin T. Instead, in all four hypertrophic models, Cdk9 activation involves the dissociation of 7SK small nuclear RNA (snRNA), an endogenous inhibitor. In culture, dominant-negative Cdk9 blocked ET-1-induced hypertrophy, whereas an anti-sense "knockdown" of 7SK snRNA provoked spontaneous cell growth. In trans-genie mice, concordant with these results, activation of Cdk9 activity via cardiac-specific overexpression of cyclin Tl suffices to provoke hypertrophy. Together, these findings implicate Cdk9 activity as a pivotal regulator of pathophysiological heart growth. Because hypertrophy, in turn, is a cardinal risk factor for developing cardiac pump failure, these results support the logic of examining Cdk9 as a potential drug target in heart disease.
...
PMID:Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. 1269 56

We recently reported that protein phosphatase 1 (PP1) dephosphorylates RNA polymerase II C-terminal repeats and regulates HIV-1 transcription in vitro. Here we provide evidence that PP1 is also required for Tat-induced HIV-1 transcription and for viral replication in cultured cells. Inhibition of PP1 by overexpression of nuclear inhibitor of PP1 (NIPP1) inhibited Tat-induced HIV-1 transcription in transient transfection assays. A mutant of NIPP1 that was defective in binding to PP1 did not have this effect. Also the co-expression of PP1 gamma reversed the inhibitory effect of NIPP1. Adeno-associated virus-mediated delivery of NIPP1 significantly reduced HIV-1 transcription induced by Tat-expressing adenovirus in CD4+ HeLa cells that contained an integrated HIV-1 promoter (HeLa MAGI cells). In addition, infection of HeLa MAGI cells with adeno-associated virus-NIPP1 prior to the infection with HIV-1 significantly reduced the level of HIV-1 replication. Our results indicate that PP1 might be a host cell factor that is required for HIV-1 viral transcription. Therefore, nuclear PP1 may represent a novel target for anti-HIV-1 therapeutics.
...
PMID:Nuclear protein phosphatase-1 regulates HIV-1 transcription. 1278 39

Messenger RNA 3'-end formation is functionally coupled to transcription by RNA polymerase II. By tagging and purifying Ref2, a non-essential protein previously implicated in mRNA cleavage and termination, we isolated a multiprotein complex, holo-CPF, containing the yeast cleavage and polyadenylation factor (CPF) and six additional polypeptides. The latter can form a distinct complex, APT, in which Pti1, Swd2, a type I protein phosphatase (Glc7), Ssu72 (a TFIIB and RNA polymerase II-associated factor), Ref2, and Syc1 are associated with the Pta1 subunit of CPF. Systematic tagging and purification of holo-CPF subunits revealed that yeast extracts contain similar amounts of CPF and holo-CPF. By purifying holo-CPF from strains lacking Ref2 or containing truncated subunits, subcomplexes were isolated that revealed additional aspects of the architecture of APT and holo-CPF. Chromatin immunoprecipitation was used to localize Ref2, Ssu72, Pta1, and other APT subunits on small nucleolar RNA (snoRNA) genes and primarily near the polyadenylation signals of the constitutively expressed PYK1 and PMA1 genes. Use of mutant components of APT revealed that Ssu72 is important for preventing readthrough-dependent expression of downstream genes for both snoRNAs and polyadenylated transcripts. Ref2 and Pta1 similarly affect at least one snoRNA transcript.
...
PMID:Organization and function of APT, a subcomplex of the yeast cleavage and polyadenylation factor involved in the formation of mRNA and small nucleolar RNA 3'-ends. 1281 4


<< Previous 1 2 3 4 5 6 7 Next >>

---