Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P23193 (transcription elongation factor)
 739 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CDK9-cyclin T kinase complex, positive transcription elongation factor b (P-TEFb), stimulates the process of elongation of RNA polymerase (Pol) II during transcription of human immunodeficiency virus. P-TEFb associates with the human immunodeficiency virus Tat protein and with the transactivation response element to form a specific complex, thereby mediating efficient elongation. Here, we show that P-TEFb preferentially phosphorylates hSPT5 as compared with the carboxyl-terminal domain of RNA Pol II in vitro. Phosphorylation of hSPT5 by P-TEFb occurred on threonine and serine residues in its carboxyl-terminal repeat domains. In addition, we provide several lines of evidence that P-TEFb is a CDK-activating kinase (CAK)-independent kinase. For example, CDK9 was not phosphorylated by CAK, whereas CDK2-cyclin A kinase activity was dramatically enhanced by CAK. Therefore, it is likely that P-TEFb participates in regulation of elongation by RNA Pol II by phosphorylation of its substrates, hSPT5 and the CTD of RNA Pol II, in a CAK-independent manner.
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PMID:Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. 1114 67

J3R, the 39-kDa subunit of vaccinia virus poly(A) polymerase, is a multifunctional protein that catalyzes (nucleoside-2'-O-)-methyltransferase activity, serves as a poly(A) polymerase stimulatory factor, and acts as a postreplicative positive transcription elongation factor. Prior results support an association between poly(A) polymerase and the virion RNA polymerase. A possible direct interaction between J3R and H4L subunit of virion RNA polymerase was evaluated. J3R was shown to specifically bind to H4L amino acids 235-256, C terminal to NPH I binding site on H4L. H4L binds to the C-terminal region of J3R between amino acids 169 and 333. The presence of a J3R binding site near to the NPH I binding region on H4L led us to evaluate a physical interaction between NPH I and J3R. The NPH I binding site was located on J3R between amino acids 169 and 249, and J3R was shown to bind to NPH I between amino acids 457 and 524. To evaluate a role for J3R in early gene mRNA synthesis, transcription termination, and/or release, a transcription-competent extract prepared from cells infected with mutant virus lacking J3R, J3-7. Analysis of transcription activity demonstrated that J3R is not required for early mRNA synthesis and is not an essential factor in early gene transcription termination or transcript release in vitro. J3R interaction with NPH I and H4L may serve as a docking site for J3R on the virion RNA polymerase, linking transcription to mRNA cap formation and poly(A) addition.
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PMID:Interaction between the J3R subunit of vaccinia virus poly(A) polymerase and the H4L subunit of the viral RNA polymerase. 1116 28

Yeast cells lacking transcription elongation factor genes such as PPR2 (TFIIS) and ELP (Elongator) are viable and show deleterious phenotypes only when transcription is rendered less effective by RNA polymerase mutations or by decreasing nucleotide pools. Here we demonstrate that deletion of the CTK1 gene, encoding the kinase subunit of RNA polymerase II carboxy-terminal domain kinase I (CTDK-I), is synthetically lethal when combined with deletion of PPR2 or ELP genes. The inviability of ctk1 elp3 double mutants can be rescued by expression of an Elp3 mutant that has retained its ability to form the Elongator complex but has severely diminished histone acetyltransferase activity, suggesting that the functional overlap between CTDK-I and Elongator is in assembly of RNA polymerase II elongation complexes. Our results suggest that CTDK-I plays an important role in transcriptional elongation in vivo, possibly by creating a form of RNA polymerase that is less prone to transcriptional arrest.
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PMID:Involvement of yeast carboxy-terminal domain kinase I (CTDK-I) in transcription elongation in vivo. 1131 53

Proteins produced in elevated amounts in response to oxacillin challenge of Staphylococcus aureus strain RN450, were studied by comparing Coomassie blue stained two-dimensional gels of cellular proteins. At least nine proteins were produced in elevated amounts following exposure to growth inhibitory concentrations of oxacillin. N-terminal sequences were obtained for five of the proteins and the databases were searched to tentatively identify them. The proteins were identified as homologs of (i) methionine sulfoxide reductase (MsrA); (ii) a signal transduction protein (TRAP) involved in regulating RNAIII production encoded by the agr locus; (iii) transcription elongation factor GreA; (iv) the heat shock protein GroES; and (v) the enzyme IIA component of the phosphoenolpyruvate:sugar phosphotransferase system. A similar induction response was observed with the other cell wall-active antibiotics, but not with antibiotics that affect other cellular targets. Increased transcription of the msrA and groEL genes in response to cell wall-active antibiotics was also demonstrated. Although net protein synthesis is inhibited subsequent to inhibition of peptidoglycan biosynthesis by cell wall-active antibiotics, some proteins are induced in S. aureus, presumably in an attempt by the cell to counter the inhibitory effects of these agents.
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PMID:Cell wall-active antibiotic induced proteins of Staphylococcus aureus identified using a proteomic approach. 1135 71

The class II transactivator (CIITA) regulates not only the transcription of HLA-DR, -DQ, -DP, but also invariant chain, DMA and DMB genes. A hybrid mutant CIITA protein, which contained residues from positions 302 to 1130 in CIITA fused to the enhanced green fluorescent protein (EdCIITA), inhibited the function of the wild-type protein. EdCIITA extinguished the inducible and constitutive expression of MHC II genes in epithelial cells treated with IFN-gamma and B lymphoblastoid cells respectively. Also, it blocked T cell activation by superantigen. This inhibition correlated with the localization of EdCIITA but not CIITA in the cytoplasm of cells. However, when EdCIITA was co-expressed with a dominant-negative form of the nucleoporin Nup214/CAN, it also accumulated in the nucleus. These data suggest that EdCIITA not only competes with the wild-type protein for the binding to MHC II promoters but sequesters a critical co-factor of CIITA in the cytoplasm. CIITA also recruits the histone acetyltransferase cAMP responsive element binding protein (CREB) binding protein and positive transcription elongation factor b (p-TEFb) for the transcription of MHC II genes. Dominant-negative p300 (DNp300) or CDK9 (DNCDK9) proteins inhibited the function of CIITA and of the DRA promoter. Thus, combinations of EdCIITA and DNp300 and/or DNCDK9 proteins extinguished the transcription of MHC II genes. They might become useful for future genetic therapeutic approaches in organ transplantation and autoimmune diseases.
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PMID:Combinations of dominant-negative class II transactivator, p300 or CDK9 proteins block the expression of MHC II genes. 1143 25

Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor in clinical trials as a cancer therapy that has been recently shown to block human immunodeficiency virus Tat transactivation and viral replication through inhibition of positive transcription elongation factor b (P-TEFb). Flavopiridol is the most potent P-TEFb inhibitor reported and the first Cdk inhibitor that is not competitive with ATP. We examined the ability of flavopiridol to inhibit P-TEFb (Cdk9/cyclin T1) phosphorylation of both RNA polymerase II and the large subunit of the 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) sensitivity-inducing factor and found that the IC(50) determined was directly related to the concentration of the enzyme. We concluded that the flavonoid associates with P-TEFb with 1:1 stoichiometry even at concentrations of enzyme in the low nanomolar range. These results indicate that the apparent lack of competition with ATP could be caused by a very tight binding of the drug. We developed a novel immobilized P-TEFb assay and demonstrated that the drug remains bound for minutes even in the presence of high salt. Flavopiridol remained bound in the presence of a 1000-fold excess of the commonly used inhibitor DRB, suggesting that the immobilized P-TEFb could be used in a simple screening assay that would allow the discovery or characterization of compounds with binding properties similar to flavopiridol. Finally, we compared the ability of flavopiridol and DRB to inhibit transcription in vivo using nuclear run-on assays and concluded that P-TEFb is required for transcription of most RNA polymerase II molecules in vivo.
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PMID:Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. 1143 68

The RNA polymerase II (pol II) transcription complex undergoes a structural transition around registers 20-25, as indicated by ExoIII footprinting analyses. We have employed a highly purified system to prepare pol II complexes stalled at very precise positions during the initial stage of transcript elongation. Using potassium permanganate we analyzed the open region ('transcription bubble') of complexes stalled between registers 15 and 35. We found that from register 15 up to 25 the transcription bubble expands concomitantly with RNA synthesis. At registers 26 and 27 the bubble has a high tendency to retract at the leading edge. Addition of transcription elongation factor TFIIS re-extends the bubble to the stall site, resulting in complexes competent for transcript elongation. These findings are discussed in the light of the recently determined structures for RNA polymerases.
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PMID:Analysis of the open region of RNA polymerase II transcription complexes in the early phase of elongation. 1143 15

Located at the 30 kb genomic region between complement factor B and component C4 are four ubiquitously expressed genes RD, SKI2W, DOM3Z and RP1. Besides RP1, the protein products of the other three genes each has highly conserved homologues or related proteins in lower eukaryotes, contains leucine zipper motifs for protein interaction, and plays important roles related to RNA metabolism. RD is a subunit of the negative transcription elongation factor, critical for the regulation of gene expression. It has an RNA recognition motif and 24 copies of Arg-Asp (RD) repeats. Ski2w is a nucleolar and cytoplasmic protein that has a putative RNA helicase domain. Fusion proteins of human Ski2w expressed in insect cells and bacteria have ATPase activity. The cytoplasmic protein of human Ski2w is associated with the polysomes and probably the 40S subunit of ribosomes. Ski2w is probably involved in the regulation of translation and RNA turnover. Dom3z is a nuclear protein whose yeast homologue forms a complex with an exoribonuclease. RP1 (or STK19) is a Ser/Thr nuclear protein kinase. No homologues of RP1 in lower eukaryotes have been discovered. Six polymorphic residues are present in human Ski2w and two in Dom3z. The potential roles of Ski2w and Dom3z on the clearance of degraded nuclear and cytoplasmic RNA raised their possibilities as susceptibility genes of systemic lupus erythematosus that is a disease with flawed processes in the removal of apoptotic materials.
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PMID:Features of the two gene pairs RD-SKI2W and DOM3Z-RP1 located between complement component genes factor B and C4 at the MHC class III region. 1148 1

Elongin is a transcription elongation factor that stimulates the rate of elongation by suppressing transient pausing by RNA polymerase II at many sites along the DNA. It is heterotrimeric in mammals, consisting of elongins A, B and C subunits, and bears overall similarity to a class of E3 ubiquitin ligases known as SCF (Skp1-Cdc53 (cullin)-F-box) complexes. A subcomplex of elongins B and C is a target for negative regulation by the von Hippel-Lindau (VHL) tumor-suppressor protein. Elongin C from Saccharomyces cerevisiae, Elc1, exhibits high sequence similarity to mammalian elongin C. Using NMR spectroscopy we have determined the three-dimensional structure of Elc1 in complex with a human VHL peptide, VHL(157-171), representing the major Elc1 binding site. The bound VHL peptide is entirely helical. Elc1 utilizes two C-terminal helices and an intervening loop to form a binding groove that fits VHL(157-171). Chemical shift perturbation and dynamics analyses reveal that a global conformational change accompanies Elc1/VHL(157-171) complex formation. Moreover, the disappearance of conformational exchange phenomena on the microsecond to millisecond time scale within Elc1 upon VHL peptide binding suggests a role for slow internal motions in ligand recognition.
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PMID:Solution structure and dynamics of yeast elongin C in complex with a von Hippel-Lindau peptide. 1154 95

To stimulate transcriptional elongation of HIV-1 genes, the transactivator Tat recruits the positive transcription elongation factor b (P-TEFb) to the initiating RNA polymerase II (RNAPII). We found that the activation of transcription by RelA also depends on P-TEFb. Similar to Tat, RelA activated transcription when tethered to RNA. Moreover, TNF-alpha triggered the recruitment of P-TEFb to the NF-kappaB-regulated IL-8 gene. While the formation of the transcription preinitiation complex (PIC) remained unaffected, DRB, an inhibitor of P-TEFb, prevented RNAPII from elongating on the IL-8 gene. Remarkably, DRB inhibition sensitized cells to TNF-alpha-induced apoptosis. Thus, NF-kappaB requires P-TEFb to stimulate the elongation of transcription and P-TEFb plays an unexpected role in regulating apoptosis.
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PMID:NF-kappaB binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. 1154 35


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