Controlling the Elongation Phase of Transcription with P-TEFb

Department of Medicine, Microbiology and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, San Francisco, California 94143, USA.
Molecular Cell (Impact Factor: 14.02). 09/2006; 23(3):297-305. DOI: 10.1016/j.molcel.2006.06.014
Source: PubMed


The positive transcription elongation factor b (P-TEFb) is a cyclin-dependent kinase that controls the elongation phase of transcription by RNA polymerase II (RNAPII). This process is made possible by the reversal of effects of negative elongation factors that include NELF and DSIF. In complex organisms, elongation control is critical for the regulated expression of most genes. In those organisms, the function of P-TEFb is influenced negatively by HEXIM proteins and 7SK snRNA and positively by a variety of recruiting factors. Phylogenetic analyses of the components of the human elongation control machinery indicate that the number of mechanisms utilized to regulate P-TEFb function increased as organisms developed more complex developmental patterns.

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    • "Accordingly, we found higher recruitment of P-TEFb to the HIV-1 LTR following cocaine treatment. The role of P-TEFb in facilitating the elongation phase of HIV-1 transcription is well established (Bourgeois et al., 2002; Fujinaga et al., 2004; Ivanov et al., 2000; Karn, 2011; Kim et al., 2002; Parada and Roeder, 1996; Peterlin and Price, 2006; Wei et al., 1998). Hence, our results demonstrate that cocaine enhances HIV-1 gene expression by inducing both the initiation and elongation phases of HIV-1 transcription by activating NF-ĸB and MSK1. "
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    ABSTRACT: Cocaine accelerates human immunodeficiency virus (HIV-1) replication by altering specific cell-signaling and epigenetic pathways. We have elucidated the underlying molecular mechanisms through which cocaine exerts its effect in myeloid cells, a major target of HIV-1 in central nervous system (CNS). We demonstrate that cocaine treatment promotes HIV-1 gene expression by activating both nuclear factor-kappa B (NF-ĸB) and mitogen- and stress-activated kinase 1 (MSK1). MSK1 subsequently catalyzes the phosphorylation of histone H3 at serine 10, and p65 subunit of NF-ĸB at 276th serine residue. These modifications enhance the interaction of NF-ĸB with P300 and promote the recruitment of the positive transcription elongation factor b (P-TEFb) to the HIV-1 LTR, supporting the development of an open/relaxed chromatin configuration, and facilitating the initiation and elongation phases of HIV-1 transcription. Results are also confirmed in primary monocyte derived macrophages (MDM). Overall, our study provides detailed insights into cocaine-driven HIV-1 transcription and replication. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 09/2015; 483. DOI:10.1016/j.virol.2015.03.036 · 3.32 Impact Factor
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    • "Transcription elongation is a key step in gene regulation and frequently deregulated during the progression of cancer (Luo et al., 2012). Not only transcription initiation, but also transcription elongation is important for efficient gene regulation(Peterlin and Price 2006; Luo et al., 2012). Transcription elongation is regulated by a variety of specific classes of transcription elongation factors that influence different classes of genes (Sims et al., 2004). "
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    ABSTRACT: The oncogene Tax of human T-cell leukemia virus type 1 (HTLV-1) is a potent transactivator of viral and cellular transcription. Here, we identified ELL2 as the sole transcription elongation factor to be specifically upregulated in HTLV-1-/Tax-transformed T-cells. Tax contributes to regulation of ELL2, since transient transfection of Tax increases ELL2 mRNA, Tax transactivates the ELL2 promoter, and repression of Tax results in decrease of ELL2 in transformed T-lymphocytes. However, we also measured upregulation of ELL2 in HTLV-1-transformed cells exhibiting undetectable amounts of Tax, suggesting that ELL2 can still be maintained independent of continuous Tax expression. We further show that Tax and ELL2 synergistically activate the HTLV-1 promoter, indicating that ELL2 cooperates with Tax in viral transactivation. This is supported by our findings that Tax and ELL2 accumulate in nuclear fractions and that they co-precipitate upon co-expression in transiently-transfected cells. Thus, upregulation of ELL2 could contribute to HTLV-1 gene regulation.
    Virology 09/2014; s 464–465:98–110. DOI:10.1016/j.virol.2014.06.028 · 3.35 Impact Factor
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    • "The overarching rationale for our screening setup was that validated hits would also be targets of existing small molecule inhibitors. CDK9 is a member of the CDK family of serine–threonine kinases that forms the catalytic core of P-TEFb and, in the presence of cyclin T, stimulates transcription elongation by RNA polymerase II (RNA Pol II) (Peterlin and Price 2006). Many small molecule drugs initially designed to target other CDKs also target CDK9, and it is now recognized that CDK9 inhibition contributes to their anti-proliferative effects (Wang and Fischer 2008). "
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    ABSTRACT: One-year survival rates for newly diagnosed hepatocellular carcinoma (HCC) are <50%, and unresectable HCC carries a dismal prognosis owing to its aggressiveness and the undruggable nature of its main genetic drivers. By screening a custom library of shRNAs directed toward known drug targets in a genetically defined Myc-driven HCC model, we identified cyclin-dependent kinase 9 (Cdk9) as required for disease maintenance. Pharmacological or shRNA-mediated CDK9 inhibition led to robust anti-tumor effects that correlated with MYC expression levels and depended on the role that both CDK9 and MYC exert in transcription elongation. Our results establish CDK9 inhibition as a therapeutic strategy for MYC-overexpressing liver tumors and highlight the relevance of transcription elongation in the addiction of cancer cells to MYC.
    Genes & development 08/2014; 28(16):1800-14. DOI:10.1101/gad.244368.114 · 10.80 Impact Factor
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