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https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#1
J Yang, B Tian, A R Brasier
Mucosal surfaces of the human body are lined by a contiguous epithelial cell surface that forms a barrier to aerosolized pathogens. Specialized pattern recognition receptors detect the presence of viral pathogens and initiate protective host responses by triggering activation of the nuclear factor κB (NFκB)/RelA transcription factor and formation of a complex with the positive transcription elongation factor (P-TEFb)/cyclin-dependent kinase (CDK)9 and Bromodomain-containing protein 4 (BRD4) epigenetic reader...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28188267/phosphorylation-of-spt5-by-cdkd-2-is-required-for-vip5-recruitment-and-normal-flowering-in-arabidopsis-thaliana
#2
Chengyuan Lu, Yongke Tian, Shiliang Wang, Yanhua Su, Ting Mao, Tongtong Huang, Qingqing Chen, Zuntao Xu, Yong Ding
The elongation factor suppressor of Ty 5 homolog (Spt5) is a regulator of transcription and histone methylation. In humans, phosphorylation of SPT5 by P-TEFb, a protein kinase composed of Cyclin-dependent kinase 9 (CDK9) and cyclin T, interacts with the RNA polymerase II-associated factor1 (PAF1) complex. However, the mechanism of SPT5 phosphorylation is not well understood in plants. Here, we examine the function of SPT5 in Arabidopsis thaliana, and find that spt5 mutant flowers early under long-day and short-day conditions...
February 10, 2017: Plant Cell
https://www.readbyqxmd.com/read/28182006/coordinate-activities-of-brd4-and-cdk9-in-the-transcriptional-elongation-complex-are-required-for-tgf%C3%AE-induced-nox4-expression-and-myofibroblast-transdifferentiation
#3
Talha Ijaz, Mohammad Jamaluddin, Yingxin Zhao, Yueqing Zhang, Jayson Jay, Celeste C Finnerty, David N Herndon, Ronald G Tilton, Allan R Brasier
Transdifferentiation of quiescent dermal fibroblasts to secretory myofibroblasts has a central role in wound healing and pathological scar formation. This myofibroblast transdifferentiation process involves TGFβ-induced de novo synthesis of alpha smooth muscle cell actin (αSMA)+ fibers that enhance contractility as well as increased expression of extracellular matrix (ECM) proteins, including collagen and fibronectin. These processes are mediated upstream by the reactive oxygen species (ROS)-producing enzyme Nox4, whose induction by TGFβ is incompletely understood...
February 9, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28178316/md-simulation-of-the-tat-cyclin-t1-cdk9-complex-revealing-the-hidden-catalytic-cavity-within-the-cdk9-molecule-upon-tat-binding
#4
Kaori Asamitsu, Takatsugu Hirokawa, Takashi Okamoto
In this study, we applied molecular dynamics (MD) simulation to analyze the dynamic behavior of the Tat/CycT1/CDK9 tri-molecular complex and revealed the structural changes of P-TEFb upon Tat binding. We found that Tat could deliberately change the local flexibility of CycT1. Although the structural coordinates of the H1 and H2 helices did not substantially change, H1', H2', and H3' exhibited significant changes en masse. Consequently, the CycT1 residues involved in Tat binding, namely Tat-recognition residues (TRRs), lost their flexibility with the addition of Tat to P-TEFb...
2017: PloS One
https://www.readbyqxmd.com/read/28165496/small-rna-directed-epigenetic-programming-of-embryonic-stem-cell-cardiac-differentiation
#5
Hossein Ghanbarian, Nicole Wagner, Jean-François Michiels, François Cuzin, Kay-Dietrich Wagner, Minoo Rassoulzadegan
Microinjection of small noncoding RNAs in one-cell embryos was reported in several instances to result in transcriptional activation of target genes. To determine the molecular mechanisms involved and to explore whether such epigenetic regulations could play a role in early development, we used a cell culture system as close as possible to the embryonic state. We report efficient cardiac differentiation of embryonic stem (ES) cells induced by small non-coding RNAs with sequences of Cdk9, a key player in cardiomyocyte differentiation...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28152383/htlv-1-tax-activates-hiv-1-transcription-in-latency-models
#6
Victor Emmanuel Viana Geddes, Diego Pandeló José, Fabio E Leal, Douglas F Nixon, Amilcar Tanuri, Renato Santana Aguiar
HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4(+) T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV...
January 30, 2017: Virology
https://www.readbyqxmd.com/read/28077651/bromodomain-containing-4-brd4-couples-nf%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#7
Bing Tian, Jun Yang, Yingxin Zhao, Teodora Ivanciuc, Hong Sun, Roberto P Garofalo, Allan R Brasier
: The airway mucosa expresses protective interferon (IFN) and inflammatory cytokines in response to Respiratory Syncytial Virus (RSV) infection. In this study, we examine the role of bromodomain containing 4 (BRD4) in mediating this innate immune response in human small airway epithelial cells. We observe that RSV induces BRD4 to complex with NFκB/RelA. BRD4 is functionally required for expression of the NFκB-dependent inflammatory gene regulatory network (GRN), including the IFN Response Factor (IRFs)-1 and -7 that mediate a cross-talk pathway for RIG-I upregulation...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28062857/positive-feedback-loop-mediated-by-protein-phosphatase-1%C3%AE-mobilization-of-p-tefb-and-basal-cdk1-drives-androgen-receptor-in-prostate-cancer
#8
Xiaming Liu, Yanfei Gao, HuiHui Ye, Sean Gerrin, Fen Ma, Yiming Wu, Tengfei Zhang, Joshua Russo, Changmeng Cai, Xin Yuan, Jihong Liu, Shaoyong Chen, Steven P Balk
P-TEFb (CDK9/cyclin T) plays a central role in androgen receptor (AR)-mediated transactivation by phosphorylating both RNA polymerase 2 complex proteins and AR at S81. CDK9 dephosphorylation mobilizes P-TEFb from an inhibitory 7SK ribonucleoprotein complex, but mechanisms targeting phosphatases to P-TEFb are unclear. We show that AR recruits protein phosphatase 1α (PP1α), resulting in P-TEFb mobilization and CDK9-mediated AR S81 phosphorylation. This increased pS81 enhances p300 recruitment, histone acetylation, BRD4 binding and subsequent further recruitment of P-TEFb, generating a positive feedback loop that sustains transcription...
January 6, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27978436/the-mtor-complex-controls-hiv-latency
#9
Emilie Besnard, Shweta Hakre, Martin Kampmann, Hyung W Lim, Nina N Hosmane, Alyssa Martin, Michael C Bassik, Erik Verschueren, Emilie Battivelli, Jonathan Chan, J Peter Svensson, Andrea Gramatica, Ryan J Conrad, Melanie Ott, Warner C Greene, Nevan J Krogan, Robert F Siliciano, Jonathan S Weissman, Eric Verdin
A population of CD4 T lymphocytes harboring latent HIV genomes can persist in patients on antiretroviral therapy, posing a barrier to HIV eradication. To examine cellular complexes controlling HIV latency, we conducted a genome-wide screen with a pooled ultracomplex shRNA library and in vitro system modeling HIV latency and identified the mTOR complex as a modulator of HIV latency. Knockdown of mTOR complex subunits or pharmacological inhibition of mTOR activity suppresses reversal of latency in various HIV-1 latency models and HIV-infected patient cells...
December 14, 2016: Cell Host & Microbe
https://www.readbyqxmd.com/read/27923747/ibulocydine-sensitizes-human-hepatocellular-carcinoma-cells-to-trail-induced-apoptosis-via-calpain-mediated-bax-cleavage
#10
Seok Soon Park, Eunjin Jwa, Seol Hwa Shin, Eun Jin Ju, Intae Park, Jhang Ho Pak, Jung Jin Hwang, Dong-Hyung Cho, B Moon Kim, Sung-Bae Kim, Jung Shin Lee, Si Yeol Song, Seong-Yun Jeong, Eun Kyung Choi
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells without affecting the majority of normal human cells. However, hepatocellular carcinoma (HCC) cells often display resistance to TRAIL-induced apoptosis. Ibulocydine (IB) is an isobutyrate ester pro-drug of a novel synthetic Cdk inhibitor that targets Cdk7 and Cdk9. In this study, we show that treatment with subtoxic doses of IB in combination with TRAIL displays potent cytotoxicity in TRAIL-resistant human HCC cells...
December 5, 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27918433/protein-phosphatase-1-regulates-expression-of-neuregulin-1
#11
Tatiana Ammosova, Kareem Washington, Jamie Rotimi, Namita Kumari, Kahli A Smith, Xiaomei Niu, Marina Jerebtsova, Sergei Nekhai
Protein phosphatase 1 (PP1), a cellular serine/threonine phosphatase, is targeted to cellular promoters by its major regulatory subunits, PP1 nuclear targeting subunit, nuclear inhibitor of PP1 (NIPP1) and RepoMan. PP1 is also targeted to RNA polymerase II (RNAPII) by NIPP1 where it can dephosphorylate RNAPII and cycle-dependent kinase 9 (CDK9). Here, we show that treatment of cells with a small molecule activator of PP1 increases the abundance of a neuregulin-1 (NRG-1)-derived peptide. NRG-1 mRNA and protein levels were increased in the cells stably or transiently expressing mutant NIPP1 (mNIPP1) that does not bind PP1, but not in the cells expressing NIPP1...
December 2, 2016: Biology
https://www.readbyqxmd.com/read/27847320/inhibition-of-cdk9-induces-apoptosis-and-potentiates-the-effect-of-cisplatin-in-hypopharyngeal-carcinoma-cells
#12
Shengda Cao, Yingyi Yu, Shangren Chen, Dapeng Lei, Shudong Wang, Xinliang Pan, Jun Peng
Myeloid cell leukemia-1 (Mcl-1) plays an important role in survival, chemo- and radioresistance of head and neck squamous cell carcinoma (HNSCC). Cyclin-dependent kinase 9/cyclin T (CDK9) promotes excessive production of multiple pro-survival proteins including Mcl-1, leading to impaired apoptosis of cancer cells. As such, CDK9 is an emerging therapeutic target in cancer therapy. We herein report the first study of targeting CDK9 as a treatment strategy for hypopharyngeal squamous cell carcinoma (HSCC), an aggressive malignancy associated with one of the worst prognoses within HNSCC...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27833949/the-emerging-picture-of-cdk9-p-tefb-more-than-20-years-of-advances-since-pitalre
#13
REVIEW
Nikolas Ferreira Dos Santos Paparidis, Maxwell Castro Durvale, Fernanda Canduri
CDK9 is a prominent member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the primary steps of mRNA synthesis and processing by eukaryotic RNA polymerase II. As a cyclin-dependent kinase, CDK9 activation in vivo depends upon its association with T-type cyclins to assemble the positive transcription elongation factor (P-TEFb). Although CDK9/P-TEFb phosphorylates the C-terminal domain of RNAP II in the same positions targeted by CDK7 (TFIIH) and CDK8 (Mediator), the former does not participate in the transcription initiation, but rather plays a unique role by driving the polymerase to productive elongation...
November 11, 2016: Molecular BioSystems
https://www.readbyqxmd.com/read/27833165/genetic-and-pharmacological-inhibition-of-cdk9-drives-neutrophil-apoptosis-to-resolve-inflammation-in-zebrafish-in-vivo
#14
Laura J Hoodless, Christopher D Lucas, Rodger Duffin, Martin A Denvir, Christopher Haslett, Carl S Tucker, Adriano G Rossi
Neutrophilic inflammation is tightly regulated and subsequently resolves to limit tissue damage and promote repair. When the timely resolution of inflammation is dysregulated, tissue damage and disease results. One key control mechanism is neutrophil apoptosis, followed by apoptotic cell clearance by phagocytes such as macrophages. Cyclin-dependent kinase (CDK) inhibitor drugs induce neutrophil apoptosis in vitro and promote resolution of inflammation in rodent models. Here we present the first in vivo evidence, using pharmacological and genetic approaches, that CDK9 is involved in the resolution of neutrophil-dependent inflammation...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27799305/heat-shock-protein-90-facilitates-latent-hiv-reactivation-through-maintaining-the-function-of-positive-transcriptional-elongation-factor-b-p-tefb-under-proteasome-inhibition
#15
Xiao-Yan Pan, Wei Zhao, Chun-Yan Wang, Jian Lin, Xiao-Yun Zeng, Ru-Xia Ren, Keng Wang, Tian-Rong Xun, Yechiel Shai, Shu-Wen Liu
The persistence of HIV in resting memory CD4(+) T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27797603/cyclin-dependent-kinases-as-therapeutic-targets-for-hiv-1-infection
#16
Andrew P Rice
A number of cyclin-dependent kinases (CDKs) mediate key steps in the HIV-1 replication cycle and therefore have potential to serve as therapeutic targets for HIV-1 infection, especially in HIV-1 cure strategies. Current HIV-1 cure strategies involve the development of small molecules that are able to activate HIV-1 from latent infection, thereby allowing the immune system to recognize and clear infected cells. Areas covered: The role of seven CDK family members in the HIV-1 replication cycle is reviewed, with a focus on CDK9, as the mechanism whereby the viral Tat protein utilizes CDK9 to enhance viral replication is known in considerable detail...
December 2016: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/27793799/brd4-mediates-nf-%C3%AE%C2%BAb-dependent-epithelial-mesenchymal-transition-and-pulmonary-fibrosis-via-transcriptional-elongation
#17
Bing Tian, Yingxin Zhao, Hong Sun, Yueqing Zhang, Jun Yang, Allan R Brasier
Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase...
December 1, 2016: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/27791144/an-evolutionary-conserved-hexim1-peptide-binds-to-the-cdk9-catalytic-site-to-inhibit-p-tefb
#18
Lydia Kobbi, Emmanuelle Demey-Thomas, Floriane Braye, Florence Proux, Olga Kolesnikova, Joelle Vinh, Arnaud Poterszman, Olivier Bensaude
The positive transcription elongation factor (P-TEFb) is required for the transcription of most genes by RNA polymerase II. Hexim proteins associated with 7SK RNA bind to P-TEFb and reversibly inhibit its activity. P-TEFb comprises the Cdk9 cyclin-dependent kinase and a cyclin T. Hexim proteins have been shown to bind the cyclin T subunit of P-TEFb. How this binding leads to inhibition of the kinase activity of Cdk9 has remained elusive, however. Using a photoreactive amino acid incorporated into proteins, we show that in live cells, cell extracts, and in vitro reconstituted complexes, Hexim1 cross-links and thus contacts Cdk9...
October 25, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27774893/opmsp-a-computational-method-integrating-protein-interaction-and-sequence-information-for-the-identification-of-novel-putative-oncogenes
#19
Lei Chen, Baoman Wang, ShaoPeng Wang, Jing Yang, Jerry Hu, ZhiQun Xie, Yuwei Wang, Tao Huang, Yu-Dong Cai
Oncogenes are genes that have the potential to cause cancer. Oncogene research can provide insight into the occurrence and development of cancer, thereby helping to prevent cancer and to design effective treatments. This study proposes a network method called the oncogene prediction method based on shortest path algorithm (OPMSP) for the identification of novel oncogenes in a large protein network built using protein-protein interaction data. Novel putative genes were extracted from the shortest paths connecting any two known oncogenes...
2016: Protein and Peptide Letters
https://www.readbyqxmd.com/read/27771926/potential-use-of-flavopiridol-in-treatment-of-chronic-diseases
#20
Thejal Srikumar, Jaya Padmanabhan
This chapter describes the potential use of flavopiridol, a CDK inhibitor with anti-inflammatory and anti-proliferative activities, in the treatment of various chronic diseases. Flavopiridol arrests cell cycle progression in the G1 or G2 phase by inhibiting the kinase activities of CDK1, CDK2, CDK4/6, and CDK7. Additionally, it binds tightly to CDK9, a component of the P-TEFb complex (CDK9/cyclin T), and interferes with RNA polymerase II activation and associated transcription. This in turn inhibits expression of several pro-survival and anti-apoptotic genes, and enhances cytotoxicity in transformed cells or differentiation in growth-arrested cells...
2016: Advances in Experimental Medicine and Biology
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