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Xiaopeng Xiong, Xin Li, Yang-An Wen, Tianyan Gao
The proper establishment of epithelial polarity allows cells to sense and respond signals that arise from the microenvironment in a spatiotemporally controlled manner. Atypical PKCs (aPKCs) are implicated as key regulators of epithelial polarity. However, the molecular mechanism underlying the negative regulation of aPKCs remains largely unknown. In this study, we demonstrated that PH domain leucine-rich repeat protein phosphatase (PHLPP), a novel family of Ser/Thr protein phosphatases, plays an important role in regulating epithelial polarity by controlling the phosphorylation of both aPKC isoforms...
October 19, 2016: Journal of Biological Chemistry
Mae L Woods, Chris P Barnes
DNA double-strand breaks are lesions that form during metabolism, DNA replication and exposure to mutagens. When a double-strand break occurs one of a number of repair mechanisms is recruited, all of which have differing propensities for mutational events. Despite DNA repair being of crucial importance, the relative contribution of these mechanisms and their regulatory interactions remain to be fully elucidated. Understanding these mutational processes will have a profound impact on our knowledge of genomic instability, with implications across health, disease and evolution...
October 2016: PLoS Computational Biology
Xuefeng Deng, Peng Xu, Wei Zou, Weiran Shen, Jianxin Peng, Kaiyu Liu, John F Engelhardt, Ziying Yan, Jianming Qiu
: Human bocavirus 1 (HBoV1), an emerging human pathogenic respiratory virus, is a member of the genus Bocaparvovirus of the Parvoviridae family. In human airway epithelia air-liquid interface (HAE-ALI) cultures, HBoV1 infection initiates a DNA damage response (DDR), activating all three phosphatidylinositol 3-kinase-related kinases (PI3KKs): ATM, ATR and DNA-PKcs. In this context, activation of PI3KKs is a requirement for amplification of the HBoV1 genome (PLoS Pathog., 2016; 12:e1005399), and HBoV1 replicates only in terminally differentiated, non-dividing cells...
October 12, 2016: Journal of Virology
Ju-Ying Tsai, Dóra Rédei, Peter Forgo, Yu Li, Andrea Vasas, Judit Hohmann, Chin-Chung Wu
Human platelets contain conventional (α and β) and novel isoforms of PKC (δ and θ), and PKC activation can result in platelet aggregation and secretion reaction that are important for thrombus formation. Several tumor-promoting Euphorbiaceae diterpenes are known to act as direct activators of PKC, but many types of such diterpenes have not been studied as platelet stimulators. In the present study, two new and five known phorbol esters were isolated from Euphorbia grandicornis. Two of the isolated phorbol esters together with compounds representing ingenane, jatrophane, and myrsinane structural types were studied on PKC activation and platelet stimulation...
October 12, 2016: Journal of Natural Products
Fatemeh Sanie-Jahromi, Iraj Saadat, Mostafa Saadat
AIMS: It has been shown that exposure to extremely-low frequency (˂300Hz) oscillating electromagnetic field (EMF) can affect gene expression. The effects of different exposure patterns of 50-Hz EMF and co-treatment of EMF plus cisplatin (CDDP) on mRNA levels of seven genes involved in DNA repair pathways (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) were evaluated. MAIN METHODS: Two 50-Hz EMF intensities (0.25 and 0.50mT), three exposure patterns (5min field-on/5min field-off, 15min field-on/15min field-off, 30min field-on continuously) and two cell lines (MCF-7 and SH-SY5Y) were used...
October 6, 2016: Life Sciences
Brenda Marquina-Sánchez, Jesús González-Jorge, Valeria Hansberg-Pastor, Talia Wegman-Ostrosky, Noemi Baranda-Ávila, Sonia Mejía-Pérez, Ignacio Camacho-Arroyo, Aliesha González-Arenas
Intracellular progesterone receptors (PRs) and protein kinases C (PKCs) are known regulators of cancer cell proliferation and metastasis. Both PRs and PKCs are found overexpressed in grade IV human astrocytomas, also known as glioblastomas, which are the most frequent and aggressive brain tumors. In the present study, we investigated whether PR activation by PKC induces the migration and invasion of glioblastoma derived cell lines and if PKCα and δ isoforms are involved in PR activation. We observed that PKC activation with tetradecanoylphorbol acetate (TPA) increases the migration and invasion capacity of two glioblastoma derived human cell lines (U251 MG and U87) and that the treatment with the PR receptor antagonist RU486 blocks these processes...
October 4, 2016: Journal of Steroid Biochemistry and Molecular Biology
Howard H Y Chang, Go Watanabe, Christina A Gerodimos, Takashi Ochi, Tom L Blundell, Stephen P Jackson, Michael R Lieber
The nonhomologous DNA end-joining (NHEJ) pathway is a key mechanism for repairing double-stranded DNA (dsDNA) breaks that occur often in eukaryotic cells. In the simplest model, these breaks are first recognized by Ku, which then interacts with other NHEJ proteins to improve their affinity at DNA ends. These include DNA-PKcs and Artemis for trimming the DNA ends; DNA polymerase μ and λ to add nucleotides; and the DNA ligase IV complex to ligate the ends with the additional factors, XRCC4 (X-ray repair cross-complementing protein 4), XLF (XRCC4-like factor/Cernunos), and PAXX (Paralog of XRCC4 and XLF)...
October 4, 2016: Journal of Biological Chemistry
Ji Cao, Guanyu Lin, Yanling Gong, Peichen Pan, Yaxi Ma, Ping Huang, Meidan Ying, Tingjun Hou, Qiaojun He, Bo Yang
Acriflavine (ACF), a known antibacterial drug, has recently been recognized as a suitable candidate for cancer chemotherapy. However, the molecular target of ACF is not fully understood, which limits its application in cancer therapy. In this study, we established a structure-specific probe-based pull-down approach to comprehensively profile the potential target of ACF, and we identified DNA dependent protein kinase catalytic subunit (DNA-PKcs) as the direct target of ACF. Since DNA-PKcs facilitates the repair process following DNA double-strand breaks, we further developed a drug combination strategy that combined ACF with the bifunctional alkylating agent melphalan, which exerted a p53-dependent synergistic efficacy against human cancer cells both in vitro and in vivo...
September 29, 2016: Cancer Letters
Andrew J Massey
The Chk1 and ATR kinases are critical mediators of the DNA damage response pathway and help protect cancer cells from endogenous and oncogene induced replication stress. Inhibitors of both kinases are currently being evaluated in clinical trials. Chk1 inhibition with V158411 increases DNA damage and activates the ATR, ATM and DNA-PKcs dependent DNA damage response pathways. Inhibiting ATR, ATM and/or DNA-PKcs has the potential to increase the therapeutic activity of Chk1 inhibitors. ATR inhibition but not ATM or DNA-PKcs inhibition potentiated the cytotoxicity of V158411 in p53 mutant and wild type human cancer cell lines...
September 28, 2016: Cancer Letters
Sameera Nallanthighal, Amit B Shirode, Julius A Judd, Ramune Reliene
Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow...
September 27, 2016: Nutrition and Cancer
Younghyun Lee, Huizi Keiko Li, Aya Masaoka, Shigeaki Sunada, Hirokazu Hirakawa, Akira Fujimori, Jac A Nickoloff, Ryuichi Okayasu
BACKGROUND AND PURPOSE: PU-H71 is a purine-scaffold Hsp90 inhibitor developed to overcome limitations of conventional Hsp90 inhibitors. This study was designed to investigate the combined effect of PU-H71 and heavy ion irradiation on human tumor and normal cells. MATERIALS AND METHODS: The effects of PU-H71 were determined by monitoring cell survival by colony formation, and DNA double-strand break (DSB) repair by γ-H2AX foci and immuno-blotting DSB repair proteins...
September 22, 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Kyusik Shin, Ki Hyung Kim, Man Soo Yoon, Dong Soo Suh, Ji Young Lee, Ari Kim, Wankyu Eo
BACKGROUND: Malignant ovarian tumor is one of the leading causes of worldwide cancer death. It is usually characterized by insidious onset and late diagnosis because of the absence of symptoms, allowing ovarian cancer cases to progress rapidly and become unresectable. The tumor suppressor, p53, plays an important role in regulating cell cycles and apoptosis. p53 is regulated by several molecules, and it interacts with other apoptotic proteins. OBJECTIVES: To compare the prognosis of ovarian serous carcinoma and evaluate the expression of DNA-PKcs, Akt3, GSK-3β, and p53 in cancerous cells...
May 2016: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
Shih-Hung Yang, Ting-Chun Kuo, Hsu Wu, Jhe-Cyuan Guo, Chiun Hsu, Chih-Hung Hsu, Yu-Wen Tien, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo
Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways...
August 28, 2016: World Journal of Gastroenterology: WJG
Bregje van Oorschot, Giovanna Granata, Simone Di Franco, Rosemarie Ten Cate, Hans M Rodermond, Matilde Todaro, Jan Paul Medema, Nicolaas A P Franken
Radiotherapy is based on the induction of lethal DNA damage, primarily DNA double-strand breaks (DSB). Efficient DSB repair via Non-Homologous End Joining or Homologous Recombination can therefore undermine the efficacy of radiotherapy. By suppressing DNA-DSB repair with hyperthermia (HT) and DNA-PKcs inhibitor NU7441 (DNA-PKcsi), we aim to enhance the effect of radiation.The sensitizing effect of HT for 1 hour at 42°C and DNA-PKcsi [1 μM] to radiation treatment was investigated in cervical and breast cancer cells, primary breast cancer sphere cells (BCSCs) enriched for cancer stem cells, and in an in vivo human tumor model...
September 1, 2016: Oncotarget
Maximilian Mimmler, Simon Peter, Alexander Kraus, Svenja Stroh, Teodora Nikolova, Nina Seiwert, Solveig Hasselwander, Carina Neitzel, Jessica Haub, Bernhard H Monien, Petra Nicken, Pablo Steinberg, Jerry W Shay, Bernd Kaina, Jörg Fahrer
PhIP is an abundant heterocyclic aromatic amine (HCA) and important dietary carcinogen. Following metabolic activation, PhIP causes bulky DNA lesions at the C8-position of guanine. Although C8-PhIP-dG adducts are mutagenic, their interference with the DNA replication machinery and the elicited DNA damage response (DDR) have not yet been studied. Here, we analyzed PhIP-triggered replicative stress and elucidated the role of the apical DDR kinases ATR, ATM and DNA-PKcs in the cellular defense response. First, we demonstrate that PhIP induced C8-PhIP-dG adducts and DNA strand breaks...
September 5, 2016: Nucleic Acids Research
D Ding, Y Zhang, J Wang, X Zhang, Y Gao, L Yin, Q Li, J Li, H Chen
Human peripheral blood lymphocytes (HPBLs) are one of the most sensitive cells to ionizing radiation (IR) in the human body, and IR-induced DNA damage and functional impairment of HPBLs are the adverse consequences of IR accidents and major side effects of radiotherapy. Phosphorylated H2AX (γH2AX) is a sensitive marker for DNA double-strand breaks, but the role and regulation of the pan-nuclear γH2AX response in HPBLs after IR remain unclear. We herein demonstrated that the pan-nuclear γH2AX signals were increased in a time- and dose-dependent manner, colocalized with >94% of TUNEL apoptotic staining, and displayed a typical apoptotic pattern in resting HPBLs after low LET X-ray IR...
2016: Cell Death Discovery
Natalie Burrows, Joseph Williams, Brian A Telfer, Julia Resch, Helen R Valentine, Richard J Fitzmaurice, Amanda Eustace, Joely Irlam, Emily J Rowling, Cuong Hoang-Vu, Catharine M West, Georg Brabant, Kaye J Williams
Anaplastic (ATC) and certain follicular thyroid-carcinomas (FTCs) are radioresistant. The Phosphatidylinositide 3-kinase (PI3K) pathway is commonly hyperactivated in thyroid-carcinomas. PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation: How PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas is unknown. Further uncertainties exist in how these interactions function under the radioresistant hypoxic microenvironment.Under normoxia/anoxia, ATC (8505c) and FTC (FTC-133) cells were irradiated, with PI3K-inhibition (via GDC-0941 and PTEN-reconstitution into PTEN-null FTC-133s) and effects on PIKK-activation, DNA-damage, clonogenic-survival and cell cycle, assessed...
August 4, 2016: Oncotarget
Alice N Weaver, Tiffiny S Cooper, Shi Wei, William R Carroll, Eben L Rosenthal, Eddy S Yang
BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clinical outcomes compared to HPV-negative disease. However, the biology underlying differences in prognosis remains unclear. METHODS: We characterized the expression of DNA-protein kinase catalytic subunit (DNA-PkCS ), a key DNA repair protein also associated with tumor progression, in 29 cases of oropharyngeal SCCs and correlated our findings with HPV status and disease recurrence...
August 10, 2016: Head & Neck
Ka Li, Xin Li, Jiguang Tian, Hongliang Wang, Jingbo Pan, Jianmin Li
The development of chemoresistance is closely linked to the plateau of the survival rate in osteosarcoma (OS) patients. CD133-positive (CD133+) OS cells are known as cancer stem cells (CSCs) in OS and exhibit the characteristic of chemoresistance. In this study, CD133+ and CD133‑negative (CD133‑) MG‑63 cells were isolated by magnetic activated cell sorting (MACS). We verified that CD133+ MG‑63 cells were more resistant to cisplatin (CDDP) than CD133‑ MG‑63 cells. DNA‑dependent protein kinase catalytic subunit (DNA‑PKcs) and P‑glycoprotein (P‑gp) were expressed at higher levels in the CD133+ MG‑63 cells compared with those levels in the CD133‑ MG‑63 cells, whereas downregulation of DNA‑PKcs by small interfering RNA (siRNA) decreased chemoresistance to CDDP and P‑gp expression at the mRNA and protein levels in these cells...
October 2016: Oncology Reports
Shaoli Wang, Tao Sheng, Siqiang Ren, Tian Tian, Wei Lu
PKMζ has been proposed to be essential for maintenance of long-term potentiation (LTP) and long-term memory (LTM). However, recent data from PKMζ-knockout mice has called this role into question. Instead, the other atypical isoform, protein kinase C iota/lambda (PKCι/λ), has emerged as a potential alternative player. Therefore, the nature of the "memory molecule" maintaining learned information remains uncertain. Here, we report knockdown (KD) of PKCι/λ and PKMζ in the dorsal hippocampus and find deficits in early expression and late maintenance, respectively, during both LTP and hippocampus-dependent LTM...
August 16, 2016: Cell Reports
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