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)

Flavopiridol, a cyclin-dependent kinase (cdk) inhibitor, can cause cell cycle arrest, induce apoptosis in cancer cells, and inhibit tumor cell growth in vivo. The present study investigated the in vitro radiosensitizing effect of flavopiridol and the underlying molecular mechanisms in a murine ovarian cancer cell line, OCA-I. Flavopiridol inhibited cell growth in a dose-dependent manner and enhanced cell radiosensitivity assessed by the clonogenic cell survival assay. A flavopiridol dose of 300 nM, given for 1 day, enhanced radiosensitivity by a factor of 2.1. Clonogenic cell survival after split-dose radiation showed that flavopiridol inhibited repair from radiation damage. In addition, flavopiridol treatment (300 nM, 1 day) resulted in decreased levels of Ku70 and Ku86 proteins that play a role in DNA repair processes, suggesting that DNA repair processes may have been disrupted by this agent. Flow cytometry analysis showed that flavopiridol (300 nM, 1 day) accumulated the cells in G(1) and G(2) phases, with a significant reduction in the S phase component. This cell cycle redistribution is likely another mechanism underlying flavopiridol-induced cell radiosensitivity. Flavopiridol down-regulated cyclin D1 and cyclin E protein levels and also inhibited phosphorylation of retinoblastoma protein, which is inconsistent with the observed cell cycle arrest. Among the cdks tested, cdk-9, the catalytic subunit of positive transcription elongation factor b, was significantly down-regulated by flavopiridol, suggesting that flavopiridol may modulate cellular transcription processes. Furthermore, flavopiridol on its own induced apoptosis in the OCA-I cells, whereas in combination with radiation, exerted no additional increase in apoptosis. Taken together, our data show that flavopiridol strongly augmented the response of ovarian carcinoma cells to radiation and that the underlying mechanisms included inhibition of sublethal DNA damage repair and cell cycle redistribution. At the molecular level, transcriptional regulation by flavopiridol may have been involved.
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PMID:Flavopiridol, a cyclin-dependent kinase inhibitor, enhances radiosensitivity of ovarian carcinoma cells. 1281 Jun 57

The transcription elongation factor TFIIS induces mRNA cleavage by enhancing the intrinsic nuclease activity of RNA polymerase (Pol) II. We have diffused TFIIS into Pol II crystals and derived a model of the Pol II-TFIIS complex from X-ray diffraction data to 3.8 A resolution. TFIIS extends from the polymerase surface via a pore to the internal active site, spanning a distance of 100 A. Two essential and invariant acidic residues in a TFIIS loop complement the Pol II active site and could position a metal ion and a water molecule for hydrolytic RNA cleavage. TFIIS also induces extensive structural changes in Pol II that would realign nucleic acids in the active center. Our results support the idea that Pol II contains a single tunable active site for RNA polymerization and cleavage, in contrast to DNA polymerases with two separate active sites for DNA polymerization and cleavage.
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PMID:Architecture of the RNA polymerase II-TFIIS complex and implications for mRNA cleavage. 1291 90

Interactions between the cyclin-dependent kinase (CDK) inhibitor flavopiridol and the proteasome inhibitor bortezomib were examined in Bcr/Abl(+) human leukemia cells. Coexposure of K562 or LAMA84 cells to subtoxic concentration of flavopiridol (150-200 nM) and bortezomib (5-8 nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in nuclear factor kappaB (NF-kappaB)/DNA binding activity; enhanced phosphorylation of SEK1/MKK4 (stress-activated protein kinase/extracellular signal-related kinase 1/mitogen-activated protein kinase kinase 4), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK); down-regulation of Bcr/Abl; and a marked reduction in signal transducer and activator of transcription 3 (STAT3) and STAT5 activity. In imatinib mesylate-resistant K562 cells displaying increased Bcr/Abl expression, bortezomib/flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and BclxL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib mesylate-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of flavopiridol to promote bortezomib-mediated Bcr/Abl down-regulation and apoptosis was mimicked by the positive transcription elongation factor-b (P-TEFb) inhibitor DRB (5,6-dichloro 1-beta-d-ribofuranosylbenzinida-sole). Finally, the bortezomib/flavopiridol regimen also potently induced apoptosis in Bcr/Abl(-) human leukemia cells. Collectively, these findings suggest that a strategy combining flavopiridol and bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies.
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PMID:Bortezomib and flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms. 1503 84

Streptococcus mutans is an important pathogen in the initiation of dental caries as the bacterium remains metabolically active when the environment becomes acidic. The mechanisms underlying this ability to survive and proliferate at low pH remain an area of intense investigation. Differential two-dimensional electrophoretic proteome analysis of S. mutans grown at steady state in continuous culture at pH 7.0 or pH 5.0 enabled the resolution of 199 cellular and extracellular protein spots with altered levels of expression. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified 167 of these protein spots. Sixty-one were associated with stress-responsive pathways involved in DNA replication, transcription, translation, protein folding and proteolysis. The 61 protein spots represented isoforms or cleavage products of 30 different proteins, of which 25 were either upregulated or uniquely expressed during acid-tolerant growth at pH 5.0. Among the unique and upregulated proteins were five that have not been previously identified as being associated with acid tolerance in S. mutans and/or which have not been studied in any detail in oral streptococci. These were the single-stranded DNA-binding protein, Ssb, the transcription elongation factor, GreA, the RNA exonuclease, polyribonucleotide nucleotidyltransferase (PnpA), and two proteinases, the ATP-binding subunit, ClpL, of the Clp family of proteinases and a proteinase encoded by the pep gene family with properties similar to the dipeptidase, PepD, of Lactobacillus helveticus. The identification of these and other differentially expressed proteins associated with an acid-tolerant-growth phenotype provides new information on targets for mutagenic studies that will allow the future assessment of their physiological significance in the survival and proliferation of S. mutans in low pH environments.
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PMID:Stress-responsive proteins are upregulated in Streptococcus mutans during acid tolerance. 1513 96

Acidic or type IIB transcriptional activation domains (AADs) increase rates of initiation as well as elongation of transcription. For the former effects, AADs bind general transcription factors and larger coactivator complexes, which position RNA polymerase II (RNAPII) at sites of initiation of transcription. For the latter effects, their ubiquitylation plays an important role. In this study, this posttranslational modification increased the binding between a prototypic AAD and the positive transcription elongation factor b (P-TEFb), which contains a C-type cyclin (CycT1, CycT2, or CycK) and Cdk9. By phosphorylating negative elongation factors and the C-terminal domain of RNAPII, P-TEFb modifies the transcription complex for efficient elongation and cotranscriptional processing of mRNA. Indeed, the activation domain of VP16 and ubiquitin bound the cyclin boxes and the C terminus in CycT1, respectively. Moreover, the artificial fusion of ubiquitin with VP16 not only increased its activity via DNA and RNA, which was reflected in increased ratios of elongated to initiated transcripts, but rescued the deleterious substitution of alanine for phenylalanine at position 442 in its AAD. Thus, the ubiquitylation of AADs increases their interaction with P-TEFb and augments rates of elongation of transcription.
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PMID:VP16 and ubiquitin; binding of P-TEFb via its activation domain and ubiquitin facilitates elongation of transcription of target genes. 1529 79

The chromatin configuration of DNA inhibits access by enzymes such as RNA polymerase II. This inhibition is alleviated by FACT, a conserved transcription elongation factor that has been found to reconfigure nucleosomes to allow transit along the DNA by RNA polymerase II, thus facilitating transcription. FACT also reorganizes nucleosomes after the passage of RNA polymerase II, as indicated by the effects of certain FACT mutations. The larger of the two subunits of FACT is Spt16/Cdc68, while the smaller is termed SSRP1 (vertebrates) or Pob3 (budding yeast). The HMG-box domain at the C terminus of SSRP1 is absent from Pob3; the function of this domain for yeast FACT is supplied by the small HMG-box protein Nhp6. In yeast, this "detachable" HMG domain is a general chromatin component, unlike FACT, which is found only in transcribed regions and associated with RNA polymerase II. The several domains of the larger FACT subunit are also likely to have different functions. Genetic studies suggest that FACT mediates nucleosome reorganization along several pathways, and reinforce the notion that protein unfolding and (or) refolding is involved in FACT activity for transcription.
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PMID:The FACT chromatin modulator: genetic and structure/function relationships. 1528 94

SII-T1 is a tissue-specific member of the transcription elongation factor S-II that is expressed specifically in male germ cells. In the present study, we have identified a protein named GRIP1tau interacting with SII-T1 by yeast two-hybrid screening. GRIP1tau is a novel isoform of glutamate receptor-interacting protein 1 (GRIP1) that associates with the cytoplasmic domain of the alpha-amino-3-hydroxy-5-methyl-4-isoaxazolepropionate (AMPA)-type glutamate receptor. GRIP1tau is a testis-specific nuclear protein that activates transcription when fused with a GAL4 DNA binding domain in GAL4-responsive reporter gene assays. The transactivation domain of GRIP1tau overlapped with the region essential for interaction with SII-T1, as revealed by co-immunoprecipitation assays. Also, transactivation by GRIP1tau was stimulated by SII-T1 in a dose-dependent manner. Therefore, we propose that GRIP1tau is a novel testis-specific transcriptional activator regulated by interaction with the testis-specific transcription elongation factor SII-T1.
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PMID:GRIP1tau, a novel PDZ domain-containing transcriptional activator, cooperates with the testis-specific transcription elongation factor SII-T1. 1550 23

Transcriptional elongation by RNA polymerase II (RNAPII) is regulated by the positive transcription elongation factor b (P-TEFb), which contains Cdk9 and a C-type cyclin (CycT1, CycT2a, CycT2b, or CycK). Whereas their N-terminal cylin boxes are almost identical, the C-terminal sequences of CycT1 and CycT2 are divergent. Previously, a histidine-rich stretch in CycT1 was found to bind the CTD of RNAPII and direct the transcriptional activity of this P-TEFb complex when tethered artificially to DNA. The global repressor PIE-1 from C. elegans blocked its effects. In this study, C-terminal truncations of CycT2 past its histidine-rich stretch, to a leucine-rich region next to its cyclin boxes, still maintained appreciable transcriptional activity. Moreover, this domain bound RNAPII via its CTD and PIE-1 blocked its effects. Thus, CycT2 not only contains two domains that target RNAPII but this substrate recognition is necessary for its transcriptional activity via DNA.
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PMID:Transcriptional activity and substrate recognition of cyclin T2 from P-TEFb. 1556 43

The human immunodeficiency virus type I (HIV-1) transactivator protein Tat is an unusual transcriptional activator that is thought to act solely by promoting RNA polymerase II processivity. Here we study the mechanism of Tat action by analyzing transcription complex (TC) assembly in vivo using chromatin immunoprecipitation assays. We find, unexpectedly, that like typical activators Tat dramatically stimulates TC assembly. Surprisingly, however, the TC formed on the HIV-1 long terminal repeat is atypical and contains TATA-box-binding protein (TBP) but not TBP-associated factors (TAFs). Tat function involves direct interaction with the cellular cofactor positive transcription elongation factor b (P-TEFb). Artificial tethering of P-TEFb subunits to HIV-1 promoter DNA or nascent RNA indicates that P-TEFb is responsible for directing assembly of a TC containing TBP but not TAFs. On the basis of this finding, we identify P-TEFb-dependent cellular promoters that also recruit TBP in the absence of TAFs. Thus, in mammalian cells transcription of protein-coding genes involves alternative TCs that differ by the presence or absence of TAFs.
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PMID:HIV-1 Tat stimulates transcription complex assembly through recruitment of TBP in the absence of TAFs. 1571 58

Estrogen receptor alpha (ERalpha) regulates transcription of specific genes and is believed to play a major role in breast tumorigenesis. We previously identified estrogen down regulated gene 1 (EDG1 (also known as HEXIM1)) using the C-terminus of ERalpha (E/F domain) as bait in yeast two-hybrid screenings. Here we report on the role of EDG1 as a coregulator of ERalpha transcriptional activity. We observe an interaction between EDG1 and ERalpha. EDG1 inhibits the transcriptional activity of ERalpha and this is dependent upon the C-terminus of EDG1. The C-terminus of EDG1/HEXIM1 was recently shown to inhibit the positive transcription elongation factor b (P-TEFb) by interacting with the cyclin T1 subunit. Here we show that ERalpha interacts with cyclin T1, cyclin T1 and ER co-occupancy on the promoter region of an ER target gene, and that this interaction plays an important role in ERalpha-induced gene expression. The interaction of ERalpha with cyclin T1 also allows ERalpha to compete with EDG1 for cyclin T1, and may release cyclin T1 from EDG1 repression. Conversely, increased EDG1 expression results in inhibition of cyclin T1 recruitment and ERalpha DNA binding. Our results support a novel functional interaction between ERalpha and cyclin T1 that is modulated by EDG1.
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PMID:The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1. 1594 Feb 64


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