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 positive transcription elongation factor b (P-TEFb) is a heterodimeric complex composed of cyclin-dependent kinase 9 and its regulator cyclin T1/2. It stimulates transcription elongation by phosphorylation of serine 2 residues in the carboxy-terminal domain of polymerase II. 7SK RNA and HEXIM proteins can antagonize transcriptional stimulation by sequestering P-TEFb in a catalytically inactive ribonucleoprotein (RNP). Here, we show that the previously uncharacterized La-related protein 7 (LARP7) has a role in 7SK-mediated regulation of transcription. LARP7 binds to the highly conserved 3'-terminal U-rich stretch of 7SK RNA and is an integral part of the 7SK RNP. On stimulation, LARP7 remains associated with 7SK RNA, whereas P-TEFb is released. Interestingly, reduction of LARP7 by RNA interference enhances transcription from cellular polymerase II promoters, as well as a TAT-dependent HIV-1 promoter. Thus, LARP7 is a negative transcriptional regulator of polymerase II genes, acting by means of the 7SK RNP system.
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PMID:The La-related protein LARP7 is a component of the 7SK ribonucleoprotein and affects transcription of cellular and viral polymerase II genes. 1848 87

Through controlling the nuclear level of active positive transcription elongation factor b (P-TEFb), the 7SK small nuclear RNA (snRNA) functions as a key regulator of RNA polymerase II transcription. Together with hexamethylene bisacetamide-inducible proteins 1/2 (HEXIM1/2), the 7SK snRNA sequesters P-TEFb into transcriptionally inactive ribonucleoprotein (RNP). In response to transcriptional stimulation, the 7SK/HEXIM/P-TEFb RNP releases P-TEFb to promote polymerase II-mediated messenger RNA synthesis. Besides transiently associating with HEXIM1/2 and P-TEFb, the 7SK snRNA stably interacts with the La-related protein 7 (Larp7) and the methylphosphate capping enzyme (MePCE). In this study, we used in vivo RNA-protein interaction assays to determine the sequence and structural elements of human 7SK snRNA directing assembly of the 7SK/MePCE/Larp7 core snRNP. MePCE interacts with the short 5'-terminal G1-U4/U106-G111 helix-tail motif and Larp7 binds to the 3'-terminal hairpin and the following U-rich tail of 7SK. The overall RNA structure and some particular nucleotides provide the information for specific binding of MePCE and Larp7. We also demonstrate that binding of Larp7 to 7SK is a prerequisite for in vivo recruitment of P-TEFb, indicating that besides providing stability for 7SK, Larp7 directly participates in P-TEFb regulation. Our results provide further explanation for the frequently observed link between Larp7 mutations and cancer development.
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PMID:RNA elements directing in vivo assembly of the 7SK/MePCE/Larp7 transcriptional regulatory snRNP. 2347 Oct 2

By phosphorylating negative elongation factors and the C-terminal domain of RNA polymerase II (RNAPII), positive transcription elongation factor b (P-TEFb), which is composed of CycT1 or CycT2 and CDK9, activates eukaryotic transcription elongation. In growing cells, it is found in active and inactive forms. In the former, free P-TEFb is a potent transcriptional coactivator. In the latter, it is inhibited by HEXIM1 or HEXIM2 in the 7SK small nuclear ribonucleoprotein (snRNP), which contains, additionally, 7SK snRNA, methyl phosphate-capping enzyme (MePCE), and La-related protein 7 (LARP7). This P-TEFb equilibrium determines the state of growth and proliferation of the cell. In this study, the release of P-TEFb from the 7SK snRNP led to increased synthesis of HEXIM1 but not HEXIM2 in HeLa cells, and this occurred only from an unannotated, proximal promoter. ChIP with sequencing revealed P-TEFb-sensitive poised RNA polymerase II at this proximal but not the previously annotated distal HEXIM1 promoter. Its immediate upstream sequences were fused to luciferase reporters and were found to be responsive to many P-TEFb-releasing compounds. The superelongation complex subunits AF4/FMR2 family member 4 (AFF4) and elongation factor RNA polymerase II 2 (ELL2) were recruited to this proximal promoter after P-TEFb release and were required for its transcriptional effects. Thus, P-TEFb regulates its own equilibrium in cells, most likely to maintain optimal cellular homeostasis.
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PMID:Release of positive transcription elongation factor b (P-TEFb) from 7SK small nuclear ribonucleoprotein (snRNP) activates hexamethylene bisacetamide-inducible protein (HEXIM1) transcription. 2451 7

The positive transcription elongation factor b (P-TEFb), comprised of cyclin-dependent kinase 9 (CDK9) and cyclins T1 (CycT1) or T2 (CycT2), activates eukaryotic transcription elongation. In growing cells, P-TEFb exists in active and inactive forms. In the latter, it is incorporated into the 7SK small nuclear ribonucleoprotein, which contains hexamethylene bisacetamide-induced proteins (HEXIM) 1 or 2, La-related protein 7 (LaRP7), methyl phosphate capping enzyme, and 7SK small nuclear RNA (7SK). HEXIM1 inhibits the kinase activity of CDK9 via interactions between 7SK, HEXIM1, and CycT1. LaRP7 and methyl phosphate capping enzyme interact with 7SK independently of HEXIM1 and P-TEFb. To analyze genetic interactions between HEXIM1 and/or LaRP7 and 7SK using a cell-based system, we established artificial heterologous RNA tethering assays in which reporter gene expression depended on interactions between selected regions of 7SK and its cognate binding partners fused to a strong activator. This system enabled us to map the HEXIM1- and LaRP7- binding regions of 7SK. Assays with various mutant 7SK plasmid targets revealed that the 5'U-Ubulge and central loop of stem-loop I or RNA motif 3 of 7SK are required for transactivation, suggesting that HEXIM1 and CycT1 form a combinatorial binding surface for 7SK. Moreover, a region in HEXIM1 C-terminal to its previously mapped RNA-binding motif was also required for interactions between HEXIM1 and 7SK. Finally, a tyrosine-to-alanine mutation in HEXIM1, which is critical for its inhibitory effect on CDK9, changed HEXIM1 into an activator. These cell-based assays elucidate this important aspect of transcription elongation in vivo.
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PMID:Genetic analysis of the structure and function of 7SK small nuclear ribonucleoprotein (snRNP) in cells. 2491 69

The small nuclear noncoding RNA (snRNA) 7SK is a highly conserved noncoding RNA of 331 nucleotides in animals, which is present in a nuclear ribonucleoprotein complex with proteins such as methylphosphate capping enzyme (MePCE), hexamethylene bisacetamide-inducible proteins 1 and 2 (HEXIM1 and HEXIM2) and La-related protein 7 (Larp7). Regulating the activity of the positive transcription elongation factor b (P-TEFb) is the key function of 7SK noncoding RNA. Recently, we have shown that 7SK snRNA over-expression reduces human embryonic kidney 293T cell line viability. Here, we attempt to monitor the expression level of 7SK snRNA in different human cell lines and cancer tissues. Examination of 7SK transcription either in cell lines or in different malignant tissues including blood (CML), breast and colon showed that 7SK expression significantly down-regulated in cancer. Similar to human cancer tissues and cell lines, 7SK transcriptional level decreased in stem cells in comparison with differentiated cell types. In this regard, over-expression of 7SK snRNA might be a powerful tool for blocking cancer progression by controlling the activity of P-TEFb.
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PMID:7SK small nuclear RNA transcription level down-regulates in human tumors and stem cells. 2775 77

A leading pharmacological strategy toward HIV cure requires "shock" or activation of HIV gene expression in latently infected cells with latency reversal agents (LRAs) followed by their subsequent clearance. In a screen for novel LRAs, we used fungal secondary metabolites as a source of bioactive molecules. Using orthogonal mass spectrometry (MS) coupled to latency reversal bioassays, we identified gliotoxin (GTX) as a novel LRA. GTX significantly induced HIV-1 gene expression in latent ex vivo infected primary cells and in CD4+ T cells from all aviremic HIV-1+ participants. RNA sequencing identified 7SK RNA, the scaffold of the positive transcription elongation factor b (P-TEFb) inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex, to be significantly reduced upon GTX treatment of CD4+ T cells. GTX directly disrupted 7SK snRNP by targeting La-related protein 7 (LARP7), releasing active P-TEFb, which phosphorylated RNA polymerase II (Pol II) C-terminal domain (CTD), inducing HIV transcription.
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PMID:Gliotoxin, identified from a screen of fungal metabolites, disrupts 7SK snRNP, releases P-TEFb, and reverses HIV-1 latency. 3285 Nov 67