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https://www.readbyqxmd.com/read/29743242/cyclin-dependent-kinase-7-cdk7-mediated-phosphorylation-of-the-cdk9-activation-loop-promotes-p-tefb-assembly-with-tat-and-proviral-hiv-reactivation
#1
Uri Mbonye, Benlian Wang, Giridharan Gokulrangan, Wuxian Shi, Sichun Yang, Jonathan Karn
The HIV trans-activator Tat recruits the host transcription elongation factor P-TEFb to stimulate proviral transcription. Phosphorylation of Thr186 on the activation loop (T-loop) of cyclin-dependent kinase 9 (CDK9) is essential for its kinase activity and assembly of CDK9 and cyclin T1 (CycT1) to form functional P-TEFb. Phosphorylation of a second highly conserved T-loop site, Ser175, alters the competitive binding of Tat and the host recruitment factor bromodomain containing 4 (BRD4) to P-TEFb. Here, we investigated the intracellular mechanisms that regulate these key phosphorylation events required for HIV transcription...
May 9, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29684085/the-kat5-acetyl-histone4-brd4-axis-silences-hiv-1-transcription-and-promotes-viral-latency
#2
Zichong Li, Uri Mbonye, Zeming Feng, Xiaohui Wang, Xiang Gao, Jonathan Karn, Qiang Zhou
The bromodomain protein Brd4 promotes HIV-1 latency by competitively inhibiting P-TEFb-mediated transcription induced by the virus-encoded Tat protein. Brd4 is recruited to the HIV LTR by interactions with acetyl-histones3 (AcH3) and AcH4. However, the precise modification pattern that it reads and the writer for generating this pattern are unknown. By examining a pool of latently infected proviruses with diverse integration sites, we found that the LTR characteristically has low AcH3 but high AcH4 content...
April 23, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29673219/hiv-tat-p-tefb-interaction-a-potential-target-for-novel-anti-hiv-therapies
#3
REVIEW
Kaori Asamitsu, Koh Fujinaga, Takashi Okamoto
Transcription is a crucial step in the life cycle of the human immunodeficiency virus type 1 (HIV 1) and is primarily involved in the maintenance of viral latency. Both viral and cellular transcription factors, including transcriptional activators, suppressor proteins and epigenetic factors, are involved in HIV transcription from the proviral DNA integrated within the host cell genome. Among them, the virus-encoded transcriptional activator Tat is the master regulator of HIV transcription. Interestingly, unlike other known transcriptional activators, Tat primarily activates transcriptional elongation and initiation by interacting with the cellular positive transcriptional elongation factor b (P-TEFb)...
April 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29649811/transcription-elongation-factor-p-tefb-is-involved-in-il-17f-signaling-in-airway-smooth-muscle-cells
#4
Masayuki Nakajima, Mio Kawaguchi, Masashi Matsuyama, Kyoko Ota, Junichi Fujita, Satoshi Matsukura, Shau-Ku Huang, Yuko Morishima, Yukio Ishii, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa
BACKGROUND: IL-17F is involved in the pathogenesis of several inflammatory diseases, including asthma and COPD. However, the effects of steroids on the function of IL-17F signaling mechanisms are largely unknown. One of the transcription elongation factors, positive transcription elongation factor b (P-TEFb) composed of cyclin T1 and cyclin-dependent kinase 9 (CDK9), is known as a novel checkpoint regulator of gene expression via bromodomain-containing protein 4 (Brd4). METHODS: Human airway smooth muscle cells were stimulated with IL-17F and the expression of IL-8 was evaluated by real-time PCR and ELISA...
April 12, 2018: International Archives of Allergy and Immunology
https://www.readbyqxmd.com/read/29588524/sumo-suppresses-and-myc-amplifies-transcription-globally-by-regulating-cdk9-sumoylation
#5
Fang Yu, Guang Shi, Shimeng Cheng, Jiwei Chen, Shwu-Yuan Wu, Zhiqiang Wang, Nansong Xia, Yunhao Zhai, Zhenxing Wang, Yu Peng, Dong Wang, James X Du, Lujian Liao, Sheng-Zhong Duan, Tieliu Shi, Jinke Cheng, Cheng-Ming Chiang, Jiwen Li, Jiemin Wong
Regulation of transcription is fundamental to the control of cellular gene expression and function. Although recent studies have revealed a role for the oncoprotein MYC in amplifying global transcription, little is known as to how the global transcription is suppressed. Here we report that SUMO and MYC mediate opposite effects upon global transcription by controlling the level of CDK9 sumoylation. On one hand, SUMO suppresses global transcription via sumoylation of CDK9, the catalytic subunit of P-TEFb kinase essential for productive transcriptional elongation...
March 27, 2018: Cell Research
https://www.readbyqxmd.com/read/29563491/rna-cytosine-methylation-and-methyltransferases-mediate-chromatin-organization-and-5-azacytidine-response-and-resistance-in-leukaemia
#6
Jason X Cheng, Li Chen, Yuan Li, Adam Cloe, Ming Yue, Jiangbo Wei, Kenneth A Watanabe, Jamile M Shammo, John Anastasi, Qingxi J Shen, Richard A Larson, Chuan He, Michelle M Le Beau, James W Vardiman
The roles of RNA 5-methylcytosine (RNA:m5 C) and RNA:m5 C methyltransferases (RCMTs) in lineage-associated chromatin organization and drug response/resistance are unclear. Here we demonstrate that the RCMTs, namely NSUN3 and DNMT2, directly bind hnRNPK, a conserved RNA-binding protein. hnRNPK interacts with the lineage-determining transcription factors (TFs), GATA1 and SPI1/PU.1, and with CDK9/P-TEFb to recruit RNA-polymerase-II at nascent RNA, leading to formation of 5-Azacitidine (5-AZA)-sensitive chromatin structure...
March 21, 2018: Nature Communications
https://www.readbyqxmd.com/read/29559581/rna-glycosidase-and-other-agents-target-tat-to-inhibit-hiv-1-transcription
#7
David Harrich, Hongping Jin
The HIV-1 tat gene encodes a small 86-104 amino acid protein depending on the HIV-1 strain. Tat is essential for HIV-1 replication through interactions with numerous cellular transcription factors. The interaction between Tat and P-TEFb, which is a cellular protein complex composed of cyclin T1 and CDK9, delivers P-TEFb to the newly transcribed viral mRNAs where phosphorylation of RNA polymerase II by CDK9 leads to highly efficient mRNA transcription. It has long been recognized that Tat is a potential anti-HIV-1 target and possibly a viral Achilles' heel...
March 20, 2018: Biochemical Journal
https://www.readbyqxmd.com/read/29557282/regulation-of-the-circadian-rhythmic-expression-of-sglt1-in-the-mouse-small-intestine-through-histone-acetylation-and-the-mrna-elongation-factor-brd4-p-tefb
#8
Hiroyuki Yamauchi, Kazue Honma, Kazuki Mochizuki, Toshinao Goda
Jejunal sodium/glucose co-transporter (Sglt1) displays circadian expression. The jejunum was collected every 4 h from mice, and we examined histone acetylation and binding of bromodomain-containing protein-4 (BRD4) around of the gene. Histone acetylation increased in the transcribed region of Sglt1 prior to induction of the gene. Furthermore, the binding of mRNA elongation factor around the gene showed circadian rhythm.
March 20, 2018: Bioscience, Biotechnology, and Biochemistry
https://www.readbyqxmd.com/read/29463681/bromodomain-containing-protein-4-independent-transcriptional-activation-by-autoimmune-regulator-aire-and-nf-%C3%AE%C2%BAb
#9
Fang Huang, Wei Shao, Koh Fujinaga, B Matija Peterlin
Autoimmune regulator (AIRE) and nuclear factor-κB (NF-κB) are transcription factors (TFs) that direct the expression of individual genes and gene clusters. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that recognizes and binds to acetylated histones. BRD4 also has been reported to promote interactions between the positive transcription elongation factor b (P-TEFb) and AIRE or P-TEFb and NF-κB subunit p65. Here, we report that AIRE and p65 bind to P-TEFb independently of BRD4. JQ1, a compound that disrupts interactions between BRD4 and acetylated proteins, does not decrease transcriptional activities of AIRE or p65...
April 6, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29425494/crosstalk-between-the-rna-methylation-and-histone-binding-activities-of-mepce-regulates-p-tefb-activation-on-chromatin
#10
Samantha B Shelton, Nakul M Shah, Nathan S Abell, Sravan K Devanathan, Marvin Mercado, Blerta Xhemalçe
RNAP II switching from the paused to the productive transcription elongation state is a pivotal regulatory step that requires specific phosphorylations catalyzed by the P-TEFb kinase. Nucleosolic P-TEFb activity is inhibited by its interaction with the ribonuclear protein complex built around the 7SK small nuclear RNA (7SK snRNP). MePCE is the RNA methyltransferase that methylates and stabilizes 7SK in the nucleosol. Here, we report that MePCE also binds chromatin through the histone H4 tail to serve as a P-TEFb activator at specific genes important for cellular identity...
February 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29414698/fret-image-correlation-spectroscopy-reveals-rnapii-independent-p-tefb-recruitment-on-chromatin
#11
Gabriel Bidaux, Corentin Le Nézet, Mariano Gonzalez Pisfil, Mélanie Henry, Alessandro Furlan, Oliver Bensaude, Bernard Vandenbunder, Laurent Héliot
Biochemical studies have revealed that the RNA Polymerase II (RNAPII) pause release is triggered by phosphorylation of the transcription machinery by the positive transcription elongation factor b (P-TEFb). However, there are no direct report that P-TEFb and RNA polymerase II interact in single living cells and the biophysical mechanisms mediating this association are still unclear. Förster resonance energy transfer (FRET) detects molecular interactions at the subcellular level. Time domain fluorescence lifetime imaging provides an accurate quantification of FRET efficiency, EFRET , because it is fluorochrome concentration-independent and insensitive to fluorescence bleed-through...
February 6, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29395063/the-augmented-r-loop-is-a-unifying-mechanism-for-myelodysplastic-syndromes-induced-by-high-risk-splicing-factor-mutations
#12
Liang Chen, Jia-Yu Chen, Yi-Jou Huang, Ying Gu, Jinsong Qiu, Hao Qian, Changwei Shao, Xuan Zhang, Jing Hu, Hairi Li, Shunmin He, Yu Zhou, Omar Abdel-Wahab, Dong-Er Zhang, Xiang-Dong Fu
Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway...
February 1, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29345523/hexim1-an-rna-controlled-protein-hub
#13
Annemieke A Michels, Olivier Bensaude
Hexim1 acts as a tumor suppressor and is involved in the regulation of innate immunity. It was initially described as a non-coding RNA-dependent regulator of transcription. Here, we detail how 7SK RNA binds to Hexim1 and turns it into an inhibitor of the positive transcription elongation factor (P-TEFb). In addition to its action on P-TEFb, it plays a role in a variety of different mechanisms: it controls the stability of transcription factor components and assists binding of transcription factors to their targets...
January 18, 2018: Transcription
https://www.readbyqxmd.com/read/29305013/transcription-insights-from-the-hiv-1-promoter
#14
Enrico Ne, Robert-Jan Palstra, Tokameh Mahmoudi
In this review, we cover transcription regulation of human immunodeficiency virus type 1 (HIV-1) gene expression, focusing on the invaluable contributions, made by HIV research over the years, toward the field of transcription. In this context, the HIV promoter can be considered to be a well-studied model promoter, which although a viral promoter, is subject to the same cellular regulatory mechanisms that modulate the transcriptional control of endogenous host cellular genes. The molecular control of HIV-1 transcription has been well studied and considerable knowledge toward development of alternative strategies for therapies aimed at eradicating both active but also latent HIV-1 has been obtained...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29209639/enhancer-remodeling-regulates-epigenetic-adaptation-and-resistance-to-mek1-2-inhibition-in-triple-negative-breast-cancer
#15
Samantha M Bevill, Jon S Zawistowski, Gary L Johnson
Kinase inhibitors targeting the mitogen/extracellular signal-regulated kinase kinase (MEK)- extracellular signal related kinase (ERK) signaling pathway have limited durability in inhibiting growth of triple-negative breast cancer. We defined genome wide enhancer remodeling following MEK inhibition capable of driving adaptive gene transcription. Targeting positive elongation factor (P-TEFb) transcriptional regulatory complex members can block enhancer remodeling making the response to MEK-ERK inhibition durable...
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29192216/bet-inhibitors-rvx-208-and-pfi-1-reactivate-hiv-1-from-latency
#16
Panpan Lu, Yinzhong Shen, He Yang, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, Hanyu Pan, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu
Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro...
November 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29091296/rn7sk-small-nuclear-rna-is-involved-in-neuronal-differentiation
#17
Zahra Bazi, Michele Bertacchi, Mozhgan Abasi, Samira Mohammadi-Yeganeh, Masoud Soleimani, Nicole Wagner, Hossein Ghanbarian
Rn7SK-mediated global transcriptional regulation, key function of this small nuclear RNA (snRNA), is mediated by inhibition of the positive transcription elongation factor b (P-TEFb). Recently, we have identified a potential anti-proliferative and tumor-suppressive function of Rn7SK. However, its possible regulatory role in development and cell programming has not been investigated so far. Here, we examined transcriptional levels of Rn7SK in different mouse organs. Interestingly, an increased expression level of the RNA was observed in the brain...
April 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29082287/flow-cytometric-analysis-of-hiv-1-transcriptional-activity-in-response-to-shrna-knockdown-in-a2-and-a72-j-lat-cell-lines
#18
Daniela Boehm, Melanie Ott
The main obstacle to eradicating HIV-1 from patients is post-integration latency (Finzi et al. , 1999). Antiretroviral treatments target only actively replicating virus, while latent infections that have low or no transcriptional activity remain untreated (Sedaghat et al. , 2007). To eliminate viral reservoirs, one strategy focuses on reversing HIV-1 latency via 'shock and kill' (Deeks, 2012). The basis of this strategy is to overcome the molecular mechanisms of HIV-1 latency by therapeutically inducing viral gene and protein expression under antiretroviral therapy and to cause selective cell death via the lytic properties of the virus, or the immune system now recognizing the infected cells...
June 5, 2017: Bio-protocol
https://www.readbyqxmd.com/read/29077158/effects-of-caloric-restriction-on-peroxisome-proliferator-activated-receptors-and-positive-transcription-elongation-factor-b-expression-in-obese-rats
#19
Y-B Yang, X-L Wu, B Ke, Y-J Huang, S-Q Chen, Y-Q Su, J Qin
OBJECTIVE: To investigate the effect of caloric restriction (CR) on expressions of peroxisome proliferators-activated receptors (PPARs) and positive transcription elongation factor b (P-TEFb) (including cyclin-dependent kinase 9 (CDK9) and cyclin T1) protein in visceral adipose tissue of obese rats. MATERIALS AND METHODS: Obese rats were induced by high-fat diet for 8 weeks. Then they were divided into three groups: Model (n=5), 50% Calorie Restricted (50% CR, n=5), Intermittent Fasting (IF) (eight cycles of 3-d fasting and 3-d refeeding, n=6) for 8 weeks...
October 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/29037489/latent-hiv-1-tar-regulates-7sk-responsive-p-tefb-target-genes-and-targets-cellular-immune-responses-in-the-absence-of-tat
#20
Sebastian Eilebrecht, Bernd-Joachim Benecke, Arndt G Benecke
The transactivating response element (TAR) structure of the nascent HIV-1 transcript is critically involved in the recruitment of inactive positive transcription elongation factor b (P-TEFb) to the promoter proximal paused RNA polymerase II. The viral transactivator Tat is responsible for subsequent P-TEFb activation in order to start efficient viral transcription elongation. In the absence of the viral transactivator of transcription (Tat), e.g., during latency or in early stages of HIV transcription, TAR mediates an interaction of P-TEFb with its inhibitor hexamethylene bis-acetamide-inducible protein 1 (HEXIM1), keeping P-TEFb in its inactive form...
October 2017: Genomics, Proteomics & Bioinformatics
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