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https://www.readbyqxmd.com/read/27923747/ibulocydine-sensitizes-human-hepatocellular-carcinoma-cells-to-trail-induced-apoptosis-via-calpain-mediated-bax-cleavage
#1
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 3, 2016: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/27918433/protein-phosphatase-1-regulates-expression-of-neuregulin-1
#2
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
#3
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...
November 12, 2016: 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
#4
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
#5
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
#6
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...
October 31, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27797603/cyclin-dependent-kinases-as-therapeutic-targets-for-hiv-1-infection
#7
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
#8
Bing Tian, Yingxin Zhao, Hong Sun, Yueqing Zhang, Jun Yang, Allan R Brasier
Chronic epithelial injury triggers a TGFβ-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGFβ induces the mesenchymal cell state, and determined its mechanism. We observe that TGFβ stimulation activates an inflammatory gene program controlled by the NFκB/RelA signaling pathway. In the mesenchymal state, NFκB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase...
October 28, 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
#9
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
#10
Lei Chen, Baoman Wang, ShaoPeng Wang, Jing Yang, Jerry Hu, ZhiQun Xie, Yuwei Wang, Tao Huang, Yu-Dong Cai, ZhiQun Xie
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...
October 21, 2016: Protein and Peptide Letters
https://www.readbyqxmd.com/read/27771926/potential-use-of-flavopiridol-in-treatment-of-chronic-diseases
#11
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
https://www.readbyqxmd.com/read/27764245/an-epigenetic-compound-library-screen-identifies-bet-inhibitors-that-promote-hsv-1-and-2-replication-by-bridging-p-tefb-to-viral-gene-promoters-through-brd4
#12
Ke Ren, Wei Zhang, Xiaoqing Chen, Yingyu Ma, Yue Dai, Yimei Fan, Yayi Hou, Ren Xiang Tan, Erguang Li
The human HSV-1 and -2 are common pathogens of human diseases. Both host and viral factors are involved in HSV lytic infection, although detailed mechanisms remain elusive. By screening a chemical library of epigenetic regulation, we identified bromodomain-containing protein 4 (BRD4) as a critical player in HSV infection. We show that treatment with pan BD domain inhibitor enhanced both HSV infection. Using JQ1 as a probe, we found that JQ1, a defined BD1 inhibitor, acts through BRD4 protein since knockdown of BRD4 expression ablated JQ1 effect on HSV infection...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27746890/discovery-of-4-6-disubstituted-pyrimidines-as-potent-inhibitors-of-the-heat-shock-factor-1-hsf1-stress-pathway-and-cdk9
#13
Carl S Rye, Nicola E A Chessum, Scott Lamont, Kurt G Pike, Paul Faulder, Julie Demeritt, Paul Kemmitt, Julie Tucker, Lorenzo Zani, Matthew D Cheeseman, Rosie Isaac, Louise Goodwin, Joanna Boros, Florence Raynaud, Angela Hayes, Alan T Henley, Emmanuel de Billy, Christopher J Lynch, Swee Y Sharp, Robert Te Poele, Lisa O' Fee, Kevin M Foote, Stephen Green, Paul Workman, Keith Jones
Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit (1) based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (25, 15 nM) in the HSF1 phenotypic assay...
August 1, 2016: MedChemComm
https://www.readbyqxmd.com/read/27731797/insights-into-hiv-1-proviral-transcription-from-integrative-structure-and-dynamics-of-the-tat-aff4-p-tefb-tar-complex
#14
Ursula Schulze-Gahmen, Ignacia Echeverria, Goran Stjepanovic, Yun Bai, Huasong Lu, Dina Schneidman-Duhovny, Jennifer A Doudna, Qiang Zhou, Andrej Sali, James H Hurley
HIV-1 Tat hijacks the human superelongation complex (SEC) to promote proviral transcription. Here we report the 5.9 Å structure of HIV-1 TAR in complex with HIV-1 Tat and human AFF4, CDK9, and CycT1. The TAR central loop contacts the CycT1 Tat-TAR recognition motif (TRM) and the second Tat Zn(2+)-binding loop. Hydrogen-deuterium exchange (HDX) shows that AFF4 helix 2 is stabilized in the TAR complex despite not touching the RNA, explaining how it enhances TAR binding to the SEC 50-fold. RNA SHAPE and SAXS data were used to help model the extended (Tat Arginine-Rich Motif) ARM, which enters the TAR major groove between the bulge and the central loop...
October 12, 2016: ELife
https://www.readbyqxmd.com/read/27715402/effects-of-cyclin-dependent-kinase-9-inhibition-on-zebrafish-larvae
#15
Gianfranco Matrone, John J Mullins, Carl S Tucker, Martin A Denvir
CDK9 is a known regulator of cellular transcription, growth and proliferation. Small molecule inhibitors are currently being developed and assessed in clinical trials as anti-cancer drugs. The zebrafish embryo provides an ideal model to explore the effects of CDK9 inhibition in-vivo. This has not been adequately explored previously at the level of a whole organism. We have compared and contrasted the effects of pharmacological and molecular inhibition of CDK9 on somatic growth, apoptosis and cellular proliferation in zebrafish larvae between 0 to 120 hours post fertilisation (hpf) using flavopiridol, a selective CDK9 antagonist, and CDK9-targeting morpholino...
October 7, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27662623/role-and-therapeutic-potential-of-cdk12-in-human-cancers
#16
Rosaria Chilà, Federica Guffanti, Giovanna Damia
Phosphorylation of the RNA polymerase II C-terminal domain by cyclin-dependent kinases (CDKs) is important for productive transcription. Deregulated transcription-CDKs have been reported in different human cancers. Until recently CDK9 was the only transcription-CDK with a causative role in cancer, but evidence is cumulating of the importance of CDK12. This review summarizes the role of CDK12 in transcription and RNA processing, in maintaining genomic stability/integrity and in tumorigenesis. CDK12 mutations have been reported in many cancers and have been suggested as a cause of defective DNA repair in ovarian carcinoma...
September 14, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/27582311/targeting-cdk9-a-promising-therapeutic-opportunity-in-prostate-cancer
#17
Muhammed Hamidur Rahaman, Malika Kumarasiri, Laychiluh Mekonnen, Mingfeng Yu, Sarah Diab, Hugo Albrecht, Robert Milne, Shudong Wang
Cyclin dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins; both being main causes of prostate cancer development and progression. In castrate resistant prostate cancer, traditional therapies that only target AR have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and anti-apoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease...
August 31, 2016: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27569395/antitumor-action-of-cdk-inhibitor-ls-007-as-a-single-agent-and-in-combination-with-abt-199-against-human-acute-leukemia-cells
#18
Shao Xie, Hui Jiang, Xiao-Wen Zhai, Fan Wei, Shu-Dong Wang, Jian Ding, Yi Chen
AIM: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. METHODS: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA...
November 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27550941/dinaciclib-induces-anaphase-catastrophe-in-lung-cancer-cells-via-inhibition-of-cyclin-dependent-kinases-1-and-2
#19
Alexey V Danilov, Shanhu Hu, Bernardo Orr, Kristina Godek, Lisa Maria Mustachio, David Sekula, Xi Liu, Masanori Kawakami, Faye M Johnson, Duane A Compton, Sarah J Freemantle, Ethan Dmitrovsky
Despite advances in targeted therapy, lung cancer remains the most common cause of cancer-related mortality in the United States. Chromosomal instability is a prominent feature in lung cancer and, because it rarely occurs in normal cells, it represents a potential therapeutic target. Our prior work discovered that lung cancer cells undergo anaphase catastrophe in response to inhibition of cyclin-dependent kinase 2 (CDK2), followed by apoptosis and reduced growth. In this study, the effects and mechanisms of the multi-CDK inhibitor dinaciclib on lung cancer cells were investigated...
November 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27515132/inhibitory-effect-of-cdk9-inhibitor-fit-039-on-hepatitis-b-virus-propagation
#20
Tomohisa Tanaka, Kaori Okuyama-Dobashi, Shuko Murakami, Wenjia Chen, Toru Okamoto, Keiji Ueda, Takamitsu Hosoya, Yoshiharu Matsuura, Akihide Ryo, Yasuhito Tanaka, Masatoshi Hagiwara, Kohji Moriishi
Current therapies for hepatitis B virus (HBV) cannot completely eliminate the HBV genome because of the stable population of covalently closed circular DNA (cccDNA) and so on. FIT-039, which is a cyclin-dependent kinase (CDK) 9 inhibitor, is known to suppress the replication of several DNA viruses including HSV, HPV and human adenovirus. In this study, we investigated the antiviral effect of FIT-039 on HBV infection. HepG2 cells expressing human sodium taurocholate cotransporting polypeptide (HepG2/NTCP cells) were infected with HBV in the presence of FIT-039...
September 2016: Antiviral Research
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