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https://www.readbyqxmd.com/read/28520795/birc6-mediates-imatinib-resistance-independently-of-mcl-1
#1
Denis O Okumu, Michael P East, Merlin Levine, Laura E Herring, Raymond Zhang, Thomas S K Gilbert, David W Litchfield, Yanping Zhang, Lee M Graves
Baculoviral IAP repeat containing 6 (BIRC6) is a member of the inhibitors of apoptosis proteins (IAPs), a family of functionally and structurally related proteins that inhibit apoptosis. BIRC6 has been implicated in drug resistance in several different human cancers, however mechanisms regulating BIRC6 have not been extensively explored. Our phosphoproteomic analysis of an imatinib-resistant chronic myelogenous leukemia (CML) cell line (MYL-R) identified increased amounts of a BIRC6 peptide phosphorylated at S480, S482, and S486 compared to imatinib-sensitive CML cells (MYL)...
2017: PloS One
https://www.readbyqxmd.com/read/28481868/prolyl-isomerase-pin1-regulates-the-stability-transcriptional-activity-and-oncogenic-potential-of-brd4
#2
X Hu, S-H Dong, J Chen, X Z Zhou, R Chen, S Nair, K P Lu, L-F Chen
BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4's stability by inhibiting its ubiquitination...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28448849/regulation-of-the-human-papillomavirus-type-16-late-promoter-by-transcriptional-elongation
#3
William K Songock, Matthew L Scott, Jason M Bodily
Transcripts from the late promoter of human papillomavirus type 16 (HPV16) are upregulated upon host cell differentiation. Differentiation-dependent transcript regulation is thought to sequester viral antigens in the uppermost epithelial layers, facilitating immune evasion. The mechanisms regulating late promoter upregulation during differentiation are poorly characterized. We show that the late promoter is upregulated at the transcriptional level and that the viral enhancer stimulates promoter activity. Using kinase inhibition and chromatin immunoprecipitation analysis, we show evidence for differentiation-dependent enhancement of transcript elongation...
April 24, 2017: Virology
https://www.readbyqxmd.com/read/28434229/the-cell-cycle-dependent-kinase-cdk9-is-a-post-exposure-drug-target-against-human-adenoviruses
#4
Vibhu Prasad, Maarit Suomalainen, Silvio Hemmi, Urs F Greber
Human adenoviruses (HAdVs) infect respiratory, gastrointestinal and urinary tracts, and give rise to eye infections and epidemic keratoconjunctivitis (EKC). They persist in lymphoid tissue, and cause morbidity and mortality in immunocompromised people. Treatments with significant post-exposure efficacy are not available. Here, we report that inhibition of the cell cycle-dependent kinase 9 (Cdk9) by RNA-interference, or the compound Flavopiridol blocked infections with HAdV-C2/5, EKC-causing HAdV-D8/37, and progeny formation in human corneal epithelial and cancer cells...
April 24, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28426094/sirt7-dependent-deacetylation-of-cdk9-activates-rna-polymerase-ii-transcription
#5
Maximilian F Blank, Sifan Chen, Fabian Poetz, Martina Schnölzer, Renate Voit, Ingrid Grummt
SIRT7 is an NAD+-dependent protein deacetylase that regulates cell growth and proliferation. Previous studies have shown that SIRT7 is required for RNA polymerase I (Pol I) transcription and pre-rRNA processing. Here, we took a proteomic approach to identify novel molecular targets and characterize the role of SIRT7 in non-nucleolar processes. We show that SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism, the majority of interactions requiring ongoing transcription...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28422315/regulation-of-the-alternative-splicing-and-function-of-cyclin-t1-by-the-serine-arginine-rich-protein-asf-sf2
#6
Jieqiong Zhou, Guozhen Gao, Panpan Hou, Chun-Mei Li, Deyin Guo
Positive transcription elongation factor-b (P-TEFb) is required for the release of RNA polymerase II (RNAPII) from its pause near the gene promoters and thus for efficient proceeding to the transcription elongation. It consists of two core subunits - CDK9 and one of T-typed or K-typed cyclin, of which, cyclin T1/CDK9 is the major and most studied combination. We have previously identified a novel splice variant of cyclin T1, cyclin T1b, which negatively regulates the transcription elongation of HIV-1 genes as well as several host genes...
April 19, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28404924/antitumor-effects-of-cyclin-dependent-kinase-9-inhibition-in-esophageal-adenocarcinoma
#7
Zhimin Tong, Devkumar Chatterjee, Defeng Deng, Omkara Veeranki, Alicia Mejia, Jaffer A Ajani, Wayne Hofstetter, Steven Lin, Sushovan Guha, Scott Kopetz, Sunil Krishnan, Dipen Maru
Role of cyclin dependent kinase 9(CDK9) as a potential target in esophageal adenocarcinoma (EAC) is unknown. We investigated CDK9 protein expression in EAC and Barrett's esophagus and role of CDK9 in oncogenic processes of EAC in vitro and in murine xenografts. The CDK9 expression was significantly higher in EAC as compared to Barrett's esophagus in patient samples. Stable shCDK9 in SKGT4 reduced proliferation by 37% at day 4, increased apoptosis at 48 hours and induced G1 cell cycle arrest at 48 hours (58...
April 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28361959/dinaciclib-potently-suppresses-mcl-1-and-selectively-induces-the-cell-death-in-human-ips-cells-without-affecting-the-viability-of-cardiac-tissue
#8
Khaled Alsayegh, Katsuhisa Matsuura, Hidekazu Sekine, Tatsuya Shimizu
Induced pluripotent stem (iPS) cells hold great potential for being a major source of cells for regenerative medicine. One major issue that hinders their advancement to clinic is the persistence of undifferentiated iPS cells in iPS-derived tissue. In this report, we show that the CDKs inhibitor, Dinaciclib, selectively eliminates iPS cells without affecting the viability of cardiac cells. We found that low nanomolar concentration of dinaciclib increased DNA damage and p53 protein levels in iPSCs. This was accompanied by negative regulation of the anti-apoptotic protein MCL-1...
March 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28326166/trail-delivery-by-msc-derived-extracellular-vesicles-is-an-effective-anticancer-therapy
#9
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-as-a-method-for-revealing-quantitative-substrate-motifs
#10
Nicole O 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 liquid chromatography-tandem mass spectrometry (LC-MS/MS) peptide sequencing (multiplex substrate profiling by mass spectrometry, MSP-MS)...
April 18, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28301263/a-stitch-in-time-and-cdk9
#11
W Douglas Cress
No abstract text is available yet for this article.
May 3, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28278048/brca1-recruitment-to-damaged-dna-sites-is-dependent-on-cdk9
#12
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)...
April 3, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28263964/total-rna-seq-to-identify-pharmacological-effects-on-specific-stages-of-mrna-synthesis
#13
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...
May 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
#14
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
#15
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 the 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, as they do not divide and therefore do not incorporate EdU into chromosomal DNA, which would obscure the detection of intranuclear HIV-1 genomes...
May 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28215221/targeting-chromatin-remodeling-in-inflammation-and-fibrosis
#16
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
#17
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
#18
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
#19
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
#20
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
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