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https://www.readbyqxmd.com/read/28087741/14-3-3sigma-contributes-to-radioresistance-by-regulating-dna-repair-and-cell-cycle-via-parp1-and-chk2
#1
Yifan Chen, Zhaomin Li, Zizheng Dong, Jenny Beebe, Ke Yang, Liwu Fu, Jian-Ting Zhang
: 14-3-3sigma has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3sigma contributes to these resistances via inhibiting apoptosis and arresting cells in G2/M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3sigma causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2/M phase following DNA-damaging treatments...
January 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28070830/mesenchymal-subtype-of-glioblastomas-with-high-dna-pkcs-expression-is-associated-with-better-response-to-radiotherapy-and-temozolomide
#2
Baptiste Pinel, Mathilde Duchesne, Julie Godet, Serge Milin, Antoine Berger, Michel Wager, Lucie Karayan-Tapon
A better understanding of the relationship between glioblastomas molecular subtypes and radio-chemotherapy is needed for the development of individualized strategies. In this study, we aimed to assess whether non-homologous end-joining (NHEJ) protein expression is associated and could predict responses to treatment of mesenchymal (MES) and proneural (PN) subtypes. Tumors from 122 patients with a glioblastoma treated at the University Hospital of Poitiers between 2002-2013 by an association of radiotherapy and temozolomide were collected...
January 10, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28062703/tas-116-a-novel-hsp90-inhibitor-selectively-enhances-radiosensitivity-of-human-cancer-cells-to-x-rays-and-carbon-ion-radiation
#3
Younghyun Lee, Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Jac A Nickoloff, Ryuichi Okayasu
Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion-irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion-irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts...
January 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28056869/protein-kinase-c-inhibitor-g%C3%A3-6976-but-not-g%C3%A3-6983-induces-the-reversion-of-e-to-n-cadherin-switch-and-metastatic-phenotype-in-melanoma-identification-of-the-role-of-protein-kinase-d1
#4
Messaouda Merzoug-Larabi, Caroline Spasojevic, Marianne Eymard, Caroline Hugonin, Christian Auclair, Manale Karam
BACKGROUND: Melanoma is a highly metastatic type of cancer that is resistant to all standard anticancer therapies and thus has a poor prognosis. Therefore, metastatic melanoma represents a significant clinical problem and requires novel and effective targeted therapies. The protein kinase C (PKC) family comprises multiple isoforms of serine/threonine kinases that possess distinct roles in cancer development and progression. In this study, we determined whether inhibition of PKC could revert a major process required for melanoma progression and metastasis; i...
January 5, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28045490/an-allosteric-inhibitor-scaffold-targeting-the-pif-pocket-of-atypical-protein-kinase-c-isoforms
#5
Jose M Arencibia, Wolfgang Fröhner, Magdalena Krupa, Daniel Pastor-Flores, Piotr Merker, Thomas Oellerich, Sonja Neimanis, Christian Schmithals, Verena Köberle, Evelyn Süß, Stefan Zeuzem, Holger Stark, Albrecht Piiper, Dalibor Odadzic, Jörg O Schulze, Ricardo M Biondi
There is a current and pressing need for improved cancer therapies. The use of small molecule kinase inhibitors and their application in combinatorial regimens represent an approach to personalized targeted cancer therapy. A number of AGC kinases, including atypical Protein Kinase C enzymes (PKCs), are validated drug targets for cancer treatment. Most drug development programs for protein kinases focus on the development of drugs that bind at the ATP-binding site. Alternatively, allosteric drugs have great potential for the development of future innovative drugs...
January 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28039020/protein-kinases-c-as-potential-host-targets-for-the-inhibition-of-chikungunya-virus-replication
#6
Rana Abdelnabi, Siti Naqiah Amrun, Lisa F P Ng, Pieter Leyssen, Johan Neyts, Leen Delang
We have shown previously that prostratin, a non-tumor promoting phorbol ester, inhibits chikungunya virus (CHIKV)-induced cytopathic effects in vitro. Prostratin is a potent activator of protein kinases C (PKC), a family of related serine/threonine kinases that regulate many cellular processes such as proliferation and apoptosis. The objective of this study was to explore the mechanism of the anti-CHIKV activity of prostratin. Prostratin reduced the production of infectious virus particles and viral protein accumulation in a dose-dependent manner at a post-entry step during virus replication...
December 27, 2016: Antiviral Research
https://www.readbyqxmd.com/read/28035050/chromatin-association-of-xrcc5-6-in-the-absence-of-dna-damage-depends-on-the-xpe-gene-product-ddb2
#7
Damiano Fantini, Shuo Huang, John M Asara, Srilata Bagchi, Pradip Raychaudhuri
Damaged DNA-binding protein 2 (DDB2), a nuclear protein, participates in both nucleotide excision repair and mRNA transcription. The transcriptional regulatory function of DDB2 is significant in colon cancer, as it regulates metastasis. To characterize the mechanism by which DDB2 participates in transcription, we investigated the protein partners in colon cancer cells. Here we show that DDB2 abundantly associates with XRCC5/6, not involving CUL4 and DNA-PKcs. A DNA-damaging agent that induces DNA double-stranded breaks (DSBs) does not affect the interaction between DDB2 and XRCC5...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27988337/micorrna-101-silences-dna-pkcs-and-sensitizes-pancreatic-cancer-cells-to-gemcitabine
#8
Hao Hu, Yuan He, Yandong Wang, Wuqiang Chen, Benshun Hu, YuanLong Gu
Gemcitabine sensitization is important for the treatment of pancreatic cancer. We have previously shown that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) over-expression causes Akt activation and gemcitabine resistance in pancreatic cancer cells. Here, we aim to downregulate DNA-PKcs via introduction of micorRNA-101 ("miR-101"). We showed that forced-expression of miR-101 downregulated DNA-PKcs and potentiated gemcitabine-induced PANC-1 pancreatic cancer cell death and apoptosis. Contrarily, miR-101 depletion through expressing antagomiR-101 in PANC-1 cells resulted in DNA-PKcs upregulation and gemcitabine resistance...
December 14, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27980111/dna-pkcs-atm-and-atr-interplay-maintains-genome-integrity-during-neurogenesis
#9
Vanessa Enriquez-Rios, Lavinia C Dumitrache, Susanna M Downing, Yang Li, Eric J Brown, Helen R Russell, Peter J McKinnon
: The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3 related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes...
December 15, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27980071/a-pkm-generated-by-calpain-cleavage-of-a-classical-pkc-is-required-for-activity-dependent-intermediate-term-facilitation-in-the-presynaptic-sensory-neuron-of-aplysia
#10
Carole A Farah, Margaret H Hastings, Tyler W Dunn, Katrina Gong, Danay Baker-Andresen, Wayne S Sossin
Atypical PKM, a persistently active form of atypical PKC, is proposed to be a molecular memory trace, but there have been few examinations of the role of PKMs generated from other PKCs. We demonstrate that inhibitors used to inhibit PKMs generated from atypical PKCs are also effective inhibitors of other PKMs. In contrast, we demonstrate that dominant-negative PKMs show isoform-specificity. A dominant-negative PKM from the classical PKC Apl I blocks activity-dependent intermediate-term facilitation (a-ITF) when expressed in the sensory neuron, while a dominant-negative PKM from the atypical PKC Apl III does not...
January 2017: Learning & Memory
https://www.readbyqxmd.com/read/27939942/regulation-of-the-dna-damage-response-by-dna-pkcs-inhibitory-phosphorylation-of-atm
#11
Yi Zhou, Ji-Hoon Lee, Wenxia Jiang, Jennie L Crowe, Shan Zha, Tanya T Paull
Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27893829/sansevieria-roxburghiana-schult-schult-f-family-asparagaceae-attenuates-type-2-diabetes-and-its-associated-cardiomyopathy
#12
Niloy Bhattacharjee, Ritu Khanra, Tarun K Dua, Susmita Das, Bratati De, M Zia-Ul-Haq, Vincenzo De Feo, Saikat Dewanjee
BACKGROUND: Sansevieria roxburghiana Schult. & Schult. F. (Family: Asparagaceae) rhizome has been claimed to possess antidiabetic activity in the ethno-medicinal literature in India. Therefore, present experiments were carried out to explore the protective role of edible (aqueous) extract of S. roxburghiana rhizome (SR) against experimentally induced type 2 diabetes mellitus (T2DM) and its associated cardiomyopathy in Wistar rats. METHODS: SR was chemically characterized by GC-MS analysis...
2016: PloS One
https://www.readbyqxmd.com/read/27882944/grk6-regulates-ros-response-and-maintains-hematopoietic-stem-cell-self-renewal
#13
Qiumin Le, Wenqing Yao, Yuejun Chen, Biao Yan, Cao Liu, Man Yuan, Yuqing Zhou, Lan Ma
G protein-coupled receptor kinases (GRKs) are critically involved in immune response through regulation of cytokine receptors in mature leukocytes, but their role in hematopoiesis is largely unknown. Here, we demonstrate that GRK6 knockout (GRK6(-/-)) mice exhibit lymphocytopenia, loss of the hematopoietic stem cell (HSC) and multiple progenitor populations. GRK6 deficiency leads to compromised lymphoid differentiation, largely owing to the impairment of HSC self-renewal. Transcriptome and proteomic analysis suggest that GRK6 is involved in reactive oxygen species signaling...
November 24, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#14
Michal Hammel, Yaping Yu, Sarvan K Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). Yet, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
December 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27866196/down-regulation-of-protein-kinase-c-%C3%AE%C2%B5-by-prolonged-incubation-with-pma-inhibits-the-proliferation-of-vascular-smooth-muscle-cells
#15
Huixuan Zhou, Yan Wang, Quanhong Zhou, Bin Wu, Aizhong Wang, Wei Jiang, Li Wang
BACKGROUND/AIMS: Phorbol myristate acetate (PMA) exerts a pleiotropic effect on the growth and differentiation of various cells. Protein kinase Cs (PKCs) plays a central role in mediating the effects of PMA on cells. The present study investigated whether the down-regulation of protein kinase C-ε (PKC-ε) is involved in the inhibition of vascular smooth muscle cell (VSMC) proliferation caused by prolonged PMA incubation. METHODS: Using cell counting, Cell Counting Kit-8 (CCK-8) and EdU incorporation assay on VSMCs, we evaluated the inhibitory effects of prolonged incubation of PMA, of lentiviruses carrying the short-hairpin RNAs (shRNA) of PKC-ε and of the PKC-ε inhibitor peptide on the proliferation and viability of cells...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27834678/receptor-species-dependent-desensitization-controls-kcnq1-kcne1-k-channels-as-downstream-effectors-of-gq-protein-coupled-receptors
#16
Marie-Cécile Kienitz, Dilyana Vladimirova, Christian Müller, Lutz Pott, Andreas Rinne
Activation of Gq protein-coupled receptors (GqPCRs) might induce divergent cellular responses, related to receptor-specific activation of different branches of the Gq signaling pathway. Receptor-specific desensitization provides a mechanism of effector modulation by restricting the spatiotemporal activation of signaling components downstream of Gq We quantified signaling events downstream of GqPCR activation with FRET-based biosensors in CHO and HEK 293 cells. KCNQ1/KCNE1 channels (IKs) were measured as a functional readout of receptor-specific activation...
December 16, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27830506/vitamin-a-as-pkc-co-factor-and-regulator-of-mitochondrial-energetics
#17
Ulrich Hammerling
For the past century, vitamin A has been considered to serve as a precursor for retinoids that facilitate vision or as a precursor for retinoic acid (RA), a signaling molecule that modulates gene expression. However, vitamin A circulates in plasma at levels that far exceed the amount needed for vision or the synthesis of nanomolar levels of RA, and this suggests that vitamin A alcohol (i.e. retinol) may possess additional biological activity. We have pursued this question for the last 20 years, and in this chapter, we unfold the story of our quest and the data that support a novel and distinct role for vitamin A (alcohol) action...
2016: Sub-cellular Biochemistry
https://www.readbyqxmd.com/read/27829224/inhibition-of-chk1-with-the-small-molecule-inhibitor-v158411-induces-dna-damage-and-cell-death-in-an-unperturbed-s-phase
#18
Joanne Wayne, Teresa Brooks, Andrew J Massey
Chk1 kinase is a critical component of the DNA damage response checkpoint and Chk1 inhibitors are currently under clinical investigation. Chk1 suppresses oncogene-induced replication stress with Chk1 inhibitors demonstrating activity as a monotherapy in numerous cancer types. Understanding the mechanism by which Chk1 inhibitors induce DNA damage and cancer cell death is essential for their future clinical development. Here we characterize the mechanism by which the novel Chk1 inhibitor (V158411) increased DNA damage and cell death in models of human cancer...
November 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27824138/b7-h1-antibodies-lose-antitumor-activity-due-to-activation-of-p38-mapk-that-leads-to-apoptosis-of-tumor-reactive-cd8-t-cells
#19
Xin Liu, Xiaosheng Wu, Siyu Cao, Susan M Harrington, Peng Yin, Aaron S Mansfield, Haidong Dong
B7-H1 (aka PD-L1) blocking antibodies have been used in treatment of human cancers through blocking B7-H1 expressed by tumor cells; however, their impact on B7-H1 expressing tumor-reactive CD8(+) T cells is still unknown. Here, we report that tumor-reactive CD8(+) T cells expressing B7-H1 are functional effector cells. In contrast to normal B7-H1 blocking antibody, B7-H1 antibodies capable of activating p38 MAPK lose their antitumor activity by deleting B7-H1(+) tumor-reactive CD8(+) T cells via p38 MAPK pathway...
November 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27810601/differential-roles-of-pkc-isoforms-pkcs-and-ca-2-in-gnrh-and-phorbol-12-myristate-13-acetate-pma-stimulation-of-p38mapk-phosphorylation-in-immortalized-gonadotrope-cells
#20
Shany Mugami, Shani Kravchook, Liat Rahamim-Ben Navi, Rony Seger, Zvi Naor
We examined the role of PKCs and Ca(2+) in GnRH-stimulated p38MAPK phosphorylation in the gonadotrope derived αT3-1 and LβT2 cell lines. GnRH induced a slow and rapid increase in p38MAPK phosphorylation in αT3-1 and LβT2 cells respectively, while PMA gave a slow response. The use of dominant negatives for PKCs and peptide inhibitors for the receptors for activated C kinase (RACKs), has revealed differential role for PKCα, PKCβII, PKCδ and PKCε in p38MAPK phosphorylation in a ligand-and cell context-dependent manner...
November 1, 2016: Molecular and Cellular Endocrinology
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