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Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin, Mary B Callanan
NFκB (Nuclear Factor- κ -light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb...
February 6, 2018: Biomedicines
Ulrich Lücking, Arne Scholz, Philip Lienau, Gerhard Siemeister, Dirk Kosemund, Rolf Bohlmann, Hans Briem, Ildiko Terebesi, Kirstin Meyer, Katja Prelle, Karsten Denner, Ulf Bömer, Martina Schäfer, Knut Eis, Ray Valencia, Stuart Ince, Franz von Nussbaum, Dominik Mumberg, Karl Ziegelbauer, Bert Klebl, Axel Choidas, Peter Nussbaumer, Matthias Baumann, Carsten Schultz-Fademrecht, Gerd Rühter, Jan Eickhoff, Michael Brands
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats...
November 8, 2017: ChemMedChem
Victoria A Church, Sigal Pressman, Mamiko Isaji, Mary Truscott, Nihal Terzi Cizmecioglu, Stephen Buratowski, Maxim V Frolov, Richard W Carthew
The cellular abundance of mature microRNAs (miRNAs) is dictated by the efficiency of nuclear processing of primary miRNA transcripts (pri-miRNAs) into pre-miRNA intermediates. The Microprocessor complex of Drosha and DGCR8 carries this out, but it has been unclear what controls Microprocessor's differential processing of various pri-miRNAs. Here, we show that Drosophila DGCR8 (Pasha) directly associates with the C-terminal domain of the RNA polymerase II elongation complex when it is phosphorylated by the Cdk9 kinase (pTEFb)...
September 26, 2017: Cell Reports
Kathrin Davari, Johannes Lichti, Christian Gallus, Franziska Greulich, N Henriette Uhlenhaut, Matthias Heinig, Caroline C Friedel, Elke Glasmacher
Activation of immune cells results in rapid functional changes, but how such fast changes are accomplished remains enigmatic. By combining time courses of 4sU-seq, RNA-seq, ribosome profiling (RP), and RNA polymerase II (RNA Pol II) ChIP-seq during T cell activation, we illustrate genome-wide temporal dynamics for ∼10,000 genes. This approach reveals not only immediate-early and posttranscriptionally regulated genes but also coupled changes in transcription and translation for >90% of genes. Recruitment, rather than release of paused RNA Pol II, primarily mediates transcriptional changes...
April 18, 2017: Cell Reports
Juan Alberto Sirvent, Ulrich Lücking
Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZD 6738 (ATR inhibitor), have recently drawn considerable attention. Whilst the interest in this underrepresented functional group in drug discovery is clearly on the rise, there remains an incomplete understanding of the medicinal-chemistry-relevant properties of sulfoximines...
April 6, 2017: ChemMedChem
Lien-Fu Lin, Jong-Shiaw Jin, Jui-Chang Chen, Chia-Chi Huang, Jeng-Horng Sheu, Wenlung Chen, Tang-Yi Tsao, Chih-Wei Hsu
Positive transcriptional elongation factor b (P-TEFb) contains the catalytic subunit cyclin-dependent kinase 9 (Cdk9) and the regulatory subunit cyclin T. Cyclin T1 and Cdk9 are the key factors of the PTEFb pathways and are overexpressed in the human head and neck carcinoma cell line. However, there have been limited studies regarding the role of cyclin T1 and Cdk9 in gastric gastrointestinal stromal tumors (GISTs). The aim of the present study was to assess the association between cyclin T1 and Cdk9 and their clinical significance in gastric GISTs...
June 2016: Molecular and Clinical Oncology
O A Shadrina, E S Knyazhanskaya, S P Korolev, M B Gottikh
Human immunodeficiency virus type 1 is known to use the transcriptional machinery of the host cell for viral gene transcription, and the only viral protein that partakes in this process is Tat, the viral trans-activator of transcription. During acute infection, the binding of Tat to the hairpin at the beginning of the transcribed viral RNA recruits the PTEFb complex, which in turn hyperphosphorylates RNA-polymerase II and stimulates transcription elongation. Along with acute infection, HIV-1 can also lead to latent infection that is characterized by a low level of viral transcription...
January 2016: Acta Naturae
Sebastian Wienerroither, Priyank Shukla, Matthias Farlik, Andrea Majoros, Bernadette Stych, Claus Vogl, HyeonJoo Cheon, George R Stark, Birgit Strobl, Mathias Müller, Thomas Decker
The transcriptional response to infection with the bacterium Listeria monocytogenes (Lm) requires cooperative signals of the type I interferon (IFN-I)-stimulated JAK-STAT and proinflammatory NF-κB pathways. Using ChIP-seq analysis, we define genes induced in Lm-infected macrophages through synergistic transcriptional activation by NF-κB and the IFN-I-activated transcription factor ISGF3. Using the Nos2 and IL6 genes as prime examples of this group, we show that NF-κB functions to recruit enzymes that establish histone marks of transcriptionally active genes...
July 14, 2015: Cell Reports
Christine Burlein, Carolyn Bahnck, Triveni Bhatt, Dennis Murphy, Peter Lemaire, Steve Carroll, Michael D Miller, Ming-Tain Lai
The viral transactivator protein (Tat) plays an essential role in the replication of human immunodeficiency type 1 virus (HIV-1) by recruiting the host positive transcription elongation factor (pTEFb) to the RNA polymerase II transcription machinery to enable an efficient HIV-1 RNA elongation process. Blockade of the interaction between Tat and pTEFb represents a novel strategy for developing a new class of antiviral agents. In this study, we developed a homogeneous assay in AlphaLISA (amplified luminescent proximity homogeneous assay) format using His-tagged pTEFb and biotinylated Tat to monitor the interaction between Tat and pTEFb...
November 15, 2014: Analytical Biochemistry
Lipeng Wu, Li Li, Bo Zhou, Zhaohui Qin, Yali Dou
Histone H2B ubiquitination plays an important role in transcription regulation. It has been shown that H2B ubiquitination is regulated by multiple upstream events associated with elongating RNA polymerase. Here we demonstrate that H2B K34 ubiquitylation by the MOF-MSL complex is part of the protein networks involved in early steps of transcription elongation. Knocking down MSL2 in the MOF-MSL complex affects not only global H2BK34ub, but also multiple cotranscriptionally regulated histone modifications. More importantly, we show that the MSL, PAF1, and RNF20/40 complexes are recruited and stabilized at active gene promoters by direct binary interactions...
June 19, 2014: Molecular Cell
Qian Dai, Guangxin Luan, Li Deng, Tingjun Lei, Han Kang, Xu Song, Yujun Zhang, Zhi-Xiong Xiao, Qintong Li
Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity...
May 8, 2014: Cell Reports
Nagini Maganti, Tomika D Moody, Agnieszka D Truax, Meghna Thakkar, Alexander M Spring, Markus W Germann, Susanna F Greer
Accumulating evidence shows the 26S proteasome is involved in the regulation of gene expression. We and others have demonstrated that proteasome components bind to sites of gene transcription, regulate covalent modifications to histones, and are involved in the assembly of activator complexes in mammalian cells. The mechanisms by which the proteasome influences transcription remain unclear, although prior observations suggest both proteolytic and non-proteolytic activities. Here, we define novel, non-proteolytic, roles for each of the three 19S heterodimers, represented by the 19S ATPases Sug1, S7, and S6a, in mammalian gene expression using the inflammatory gene CIITApIV...
2014: PloS One
Camille L Novis, Nancie M Archin, Maria J Buzon, Eric Verdin, June L Round, Mathias Lichterfeld, David M Margolis, Vicente Planelles, Alberto Bosque
BACKGROUND: Toll-like receptors (TLRs) are crucial for recognition of pathogen-associated molecular patterns by cells of the innate immune system. TLRs are present and functional in CD4⁺ T cells. Memory CD4⁺ T cells, predominantly central memory cells (TCM), constitute the main reservoir of latent HIV-1. However, how TLR ligands affect the quiescence of latent HIV within central memory CD4⁺ T cells has not been studied. RESULTS: We evaluated the ability of a broad panel of TLR agonists to reactivate latent HIV-1...
2013: Retrovirology
Paola Y Bertucci, A Silvina Nacht, Mariano Alló, Luciana Rocha-Viegas, Cecilia Ballaré, Daniel Soronellas, Giancarlo Castellano, Roser Zaurin, Alberto R Kornblihtt, Miguel Beato, Guillermo P Vicent, Adali Pecci
Steroid receptors were classically described for regulating transcription by binding to target gene promoters. However, genome-wide studies reveal that steroid receptors-binding sites are mainly located at intragenic regions. To determine the role of these sites, we examined the effect of progestins on the transcription of the bcl-x gene, where only intragenic progesterone receptor-binding sites (PRbs) were identified. We found that in response to hormone treatment, the PR is recruited to these sites along with two histone acetyltransferases CREB-binding protein (CBP) and GCN5, leading to an increase in histone H3 and H4 acetylation and to the binding of the SWI/SNF complex...
July 2013: Nucleic Acids Research
Serena Massari, Stefano Sabatini, Oriana Tabarrini
HIV-1 infection can be effectively controlled by HAART, which improves the quality of lives of infected individuals, but fails to completely eradicate the virus, even after decades of treatment. This issue, together with the emergence of multi-drug-resistant viruses, clearly underscores the continuing need to find novel agents able to target vulnerable steps in the viral replication cycle. HIV transcriptional regulation is a crucial step required to re-initiate viral replication from post-integration latency after interruption of therapy and to keep the virus in circulation...
2013: Current Pharmaceutical Design
Ballachanda N Devaiah, Dinah S Singer
The RNA polymerase II (Pol II) C-terminal domain (CTD) serves as a docking site for numerous proteins, bridging various nuclear processes to transcription. The recruitment of these proteins is mediated by CTD phospho-epitopes generated during transcription. The mechanisms regulating the kinases that establish these phosphorylation patterns on the CTD are not known. We report that three CTD kinases, CDK7, CDK9, and BRD4, engage in cross-talk, modulating their subsequent CTD phosphorylation. BRD4 phosphorylates PTEFb/CDK9 at either Thr-29 or Thr-186, depending on its relative abundance, which represses or activates CDK9 CTD kinase activity, respectively...
November 9, 2012: Journal of Biological Chemistry
Eduardo Mascareno, Josephine Galatioto, Inna Rozenberg, Louis Salciccioli, Haroon Kamran, Jason M Lazar, Fang Liu, Thierry Pedrazzini, M A Q Siddiqui
It is well known that the renin-angiotensin system contributes to left ventricular hypertrophy and fibrosis, a major determinant of myocardial stiffness. TGF-β1 and renin-angiotensin system signaling alters the fibroblast phenotype by promoting its differentiation into morphologically distinct pathological myofibroblasts, which potentiates collagen synthesis and fibrosis and causes enhanced extracellular matrix deposition. However, the atrial natriuretic peptide, which is induced during left ventricular hypertrophy, plays an anti-fibrogenic and anti-hypertrophic role by blocking, among others, the TGF-β-induced nuclear localization of Smads...
April 13, 2012: Journal of Biological Chemistry
Soichiro Yamamura, Sharanjot Saini, Shahana Majid, Hiroshi Hirata, Koji Ueno, Guoren Deng, Rajvir Dahiya
MicroRNA-34a (miR-34a), a potent mediator of tumor suppressor p53, has been reported to function as a tumor suppressor and miR-34a was found to be downregulated in prostate cancer tissues. We studied the functional effects of miR-34a on c-Myc transcriptional complexes in PC-3 prostate cancer cells. Transfection of miR-34a into PC-3 cells strongly inhibited in vitro cell proliferation, cell invasion and promoted apoptosis. Transfection of miR-34a into PC-3 cells also significantly inhibited in vivo xenograft tumor growth in nude mice...
2012: PloS One
Yue Zhang, Ayesha Murshid, Thomas Prince, Stuart K Calderwood
Heat shock factor 1 (HSF1) regulates one of the major pathways of protein quality control and is essential for deterrence of protein-folding disorders, particularly in neuronal cells. However, HSF1 activity declines with age, a change that may open the door to progression of neurodegenerative disorders such as Huntington's disease. We have investigated mechanisms of HSF1 regulation that may become compromised with age. HSF1 binds stably to the catalytic domain of protein kinase A (PKAcα) and becomes phosphorylated on at least one regulatory serine residue (S320)...
2011: PloS One
Richard D Palermo, Helen M Webb, Michelle J West
Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active...
October 2011: PLoS Pathogens
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