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https://www.readbyqxmd.com/read/28326166/trail-delivery-by-msc-derived-extracellular-vesicles-is-an-effective-anticancer-therapy
#1
ZhengQiang Yuan, Krishna K Kolluri, Kate H C Gowers, Sam M Janes
Extracellular vesicles (EVs) are lipid membrane-enclosed nanoparticles released by cells. They mediate intercellular communication by transferring biological molecules and therefore have potential as innovative drug delivery vehicles. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of cancer cells. Unfortunately, the clinical application of recombinant rTRAIL has been hampered by its low bioavailability and resistance of cancer cells. EV-mediated TRAIL delivery may circumvent these problems...
2017: Journal of Extracellular Vesicles
https://www.readbyqxmd.com/read/28322550/multiplex-substrate-profiling-by-mass-spectrometry-for-kinases-reveals-quantitative-substrate-motifs
#2
Nicole Olson Meyer, Anthony J O'Donoghue, Ursula Schulze-Gahmen, Matthew Ravalin, Steven M Moss, Michael B Winter, Giselle M Knudsen, Charles S Craik
The more than 500 protein kinases comprising the human kinome catalyze hundreds of thousands of phosphorylation events to regulate a diversity of cellular functions; however, the extended substrate specificity is still unknown for many of these kinases. We report here a method for quantitatively describing kinase substrate specificity using an unbiased peptide library-based approach with direct measurement of phosphorylation by tandem LC-MS/MS peptide sequencing (Multiplex Substrate Profiling by Mass Spectrometry, MSP-MS)...
March 21, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28301263/a-stitch-in-time-and-cdk9
#3
W Douglas Cress
No abstract text is available yet for this article.
March 16, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28278048/brca1-recruitment-to-damaged-dna-sites-is-dependent-on-cdk9
#4
Thales C Nepomuceno, Vanessa C Fernandes, Thiago T Gomes, Renato S Carvalho, Guilherme Suarez-Kurtz, Alvaro N Monteiro, Marcelo A Carvalho
Double strand break lesions, the most toxic type of DNA damage, are repaired primarily through 2 distinct pathways: homology-directed recombination (HR) and non-homologous end-joining (NHEJ). BRCA1 and 53BP1, 2 proteins containing the BRCT modular domain, play an important role in DNA damage response (DDR) by orchestrating the decision between HR and NHEJ, but the precise mechanisms regarding both pathways are not entirely understood. Previously, our group identified a putative interaction between BRCA1 and BARD1 (BRCA1-associated RING domain 1) and the cyclin-dependent kinase (CDK9)...
February 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28263964/total-rna-seq-to-identify-pharmacological-effects-on-specific-stages-of-mrna-synthesis
#5
Sarah A Boswell, Andrew Snavely, Heather M Landry, L Stirling Churchman, Jesse M Gray, Michael Springer
Pharmacological perturbation is a powerful tool for understanding mRNA synthesis, but identification of the specific steps of this multi-step process that are targeted by small molecules remains challenging. Here we applied strand-specific total RNA sequencing (RNA-seq) to identify and distinguish specific pharmacological effects on transcription and pre-mRNA processing in human cells. We found unexpectedly that the natural product isoginkgetin, previously described as a splicing inhibitor, inhibits transcription elongation...
March 6, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28262505/distinct-roles-of-brd2-and-brd4-in-potentiating-the-transcriptional-program-for-th17-cell-differentiation
#6
Ka Lung Cheung, Fan Zhang, Anbalagan Jaganathan, Rajal Sharma, Qiang Zhang, Tsuyoshi Konuma, Tong Shen, June-Yong Lee, Chunyan Ren, Chih-Hung Chen, Geming Lu, Matthew R Olson, Weijia Zhang, Mark H Kaplan, Dan R Littman, Martin J Walsh, Huabao Xiong, Lei Zeng, Ming-Ming Zhou
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28250118/imaging-hiv-1-genomic-dna-from-entry-through-productive-infection
#7
Ryan D Stultz, Jennifer J Cenker, David McDonald
In order to track the fate of HIV-1 particles from early entry events through productive infection, we developed a method to visualize HIV-1 DNA reverse transcription complexes by incorporation and fluorescent labeling of the thymidine analog 5-ethynyl-2' -deoxyuridine (EdU) into nascent viral DNA during cellular entry. Monocyte-derived macrophages were chosen as natural targets of HIV-1 which do not divide and therefore do not incorporate the EdU into chromosomal DNA, which would obscure detection of intranuclear HIV-1 genomes...
March 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#8
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
#9
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 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
#10
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
#11
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
#12
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
#13
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/brd4-couples-nf-%C3%AE%C2%BAb-rela-with-airway-inflammation-and-the-irf-rig-i-amplification-loop-in-respiratory-syncytial-virus-infection
#14
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 NF-κB/RelA. BRD4 is functionally required for expression of the NF-κB-dependent inflammatory gene regulatory network (GRN), including the IFN response factor 1 (IRF1) and IRF7, which mediate a cross talk pathway for RIG-I upregulation...
March 15, 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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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