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Ribonucleotide reductase

Sarah E Fordham, Helen J Blair, Claire J Elstob, Ruth Plummer, Yvette Drew, Nicola J Curtin, Olaf Heidenreich, Deepali Pal, David Jamieson, Catherine Park, John Pollard, Scott Fields, Paul Milne, Graham H Jackson, Helen J Marr, Tobias Menne, Gail L Jones, James M Allan
The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression...
May 22, 2018: Blood Advances
Maciej Gagat, Adrian Krajewski, Dariusz Grzanka, Alina Grzanka
Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients...
May 16, 2018: Oncology Reports
Cheng-Han Yu, Chi-Chi Chou, Hsin-Fang Tu, Wei-Chieh Huang, Ya-Yeh Ho, Kay-Hooi Khoo, Ming-Shyue Lee, Geen-Dong Chang
Afatinib, used for the first-line treatment of non-small-cell lung carcinoma (NSCLC) patients with distinct epidermal growth factor receptor (EGFR) mutations, inactivates EGFR by mimicking ATP structure and forming a covalent adduct with EGFR. We developed a method to unravel potential targets of afatinib in NSCLC cells through immunoprecipitation of afatinib-labeling proteins with anti-afatinib antiserum and mass spectrometry analysis. Ribonucleotide reductase (RNR) is one of target proteins of afatinib revealed by this method...
April 20, 2018: Oncotarget
Junfeng Li, Jinglin Pang, Yongdong Liu, Jing Zhang, Chuanguang Zhang, Gang Shen, Lili Song
Ribonucleotide reductase regulatory subunit M2 (RRM2) is a rate‑limiting enzyme for DNA synthesis and repair. RRM2 has vital roles in controlling the progression of cancer. In the present study, we investigated the RRM2 level in neuroblastoma tissues, analyzed its relationship with clinicopathological characteristics of neuroblastoma patients, and explored the effect of RRM2 on the biological functions of neuroblastoma cells. RRM2 levels in 67 pairs of neuroblastoma and matched adjacent non‑cancerous tissues were detected by qRT‑PCR, and its association with patient clinicopathological features was assessed...
May 8, 2018: Oncology Reports
Jonathan Muri, Sebastian Heer, Mai Matsushita, Lea Pohlmeier, Luigi Tortola, Tobias Fuhrer, Marcus Conrad, Nicola Zamboni, Jan Kisielow, Manfred Kopf
The thioredoxin-1 (Trx1) system is an important contributor to cellular redox balance and is a sensor of energy and glucose metabolism. Here we show critical c-Myc-dependent activation of the Trx1 system during thymocyte and peripheral T-cell proliferation, but repression during T-cell quiescence. Deletion of thioredoxin reductase-1 (Txnrd1) prevents expansion the CD4- CD8- thymocyte population, whereas Txnrd1 deletion in CD4+ CD8+ thymocytes does not affect further maturation and peripheral homeostasis of αβT cells...
May 10, 2018: Nature Communications
Tahmeena Khan, Iqbal Azad, Rumana Ahmad, Saman Raza, Shalini Dixit, Seema Joshi, Abdul Rahman Khan
Mixed-ligand metal (II) (M=Cu, Fe, Co and Zn) complexes containing 2-butanone thiosemicarbazone and 1, 10-phenanthroline have been synthesized and characterized by melting point, FT-IR, 1 H-NMR, UV-spectrophotometry and molar conductance measurements. All the complexes were soluble in DMSO and DMF. They were thermally stable with high melting points. The computational studies of the complexes were also performed to assess toxicity potential, bioactivity score prediction and drug likeliness assessment based on various drug filters...
2018: EXCLI Journal
Chiu-Chun Chang, Chun-Che Lin, Chia-Hung Wang, Chi-Chou Huang, Tao-Wei Ke, Po-Li Wei, Ken-Tu Yeh, Kai-Cheng Hsu, Nan-Yung Hsu, Ya-Wen Cheng
Colorectal cancer (CRC) ranks as the third-leading cause of cancer-associated mortalities in Taiwan. The expression of ribonucleotide reductase M2 ( RRM2 ) and p53R2 is associated with tumoral malignancy and progression in several types of cancer. The aim of the present study was to determine the association of p53R2/RRM2 with the upstream expression of microRNA ( miR)-211 and the association of expression levels of p53, APC and k-ras with clinical outcomes in patients with CRC. The study consisted of 192 tumor tissue samples obtained from patients with CRC...
May 2018: Oncology Letters
Makoto Kawamoto, Masayo Umebayashi, Hiroto Tanaka, Norihiro Koya, Sinichiro Nakagawa, Ken Kawabe, Hideya Onishi, Masafumi Nakamura, Takashi Morisaki
BACKGROUND/AIM: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram-like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). MATERIALS AND METHODS: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA...
May 2018: Anticancer Research
Mackenzie J Parker, Ailiena O Maggiolo, William C Thomas, Albert Kim, Steve P Meisburger, Nozomi Ando, Amie K Boal, JoAnne Stubbe
The high fidelity of DNA replication and repair is attributable, in part, to the allosteric regulation of ribonucleotide reductases (RNRs) that maintains proper deoxynucleotide pool sizes and ratios in vivo. In class Ia RNRs, ATP (stimulatory) and dATP (inhibitory) regulate activity by binding to the ATP-cone domain at the N terminus of the large α subunit and altering the enzyme's quaternary structure. Class Ib RNRs, in contrast, have a partial cone domain and have generally been found to be insensitive to dATP inhibition...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yueting Wu, Jin Sun, Anjie Li, Dandan Chen
Peripheral vascular disease (PVD) is a prevalent vascular disease that affect a large number of patients. The establishment of optimal treatments to mitigate the intimal hyperplasia (IH)-induced restenosis would help relieve the health burden of the PVD. Ribonucleotide reductase M2 (RRM2) is critical to cellular migration and proliferation. We have previously demonstrated that suppression of RRM2 expression could substantially inhibit hepatocellular carcinoma cell proliferation and migration. We hereby developed RRM2 small interfering RNA (siRNA)-loaded cell penetrating peptides-conjugated liposome-polycation-DNA complex (LPD) (RRM2-CLPD), aiming to inhibit the migration and proliferation of vascular smooth muscle cells (VSMCs) crucial for IH...
April 24, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Katarzyna Malarz, Anna Mrozek-Wilczkiewicz, Maciej Serda, Marta Rejmund, Jaroslaw Polanski, Robert Musiol
Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase...
April 3, 2018: Oncotarget
Percival Yang-Ting Chen, Michael A Funk, Edward J Brignole, Catherine L Drennan
Ribonucleotide reductases (RNRs) convert ribonucleotides to deoxynucleotides, a process essential for DNA biosynthesis and repair. Class Ia RNRs require two dimeric subunits for activity, an α2 subunit that houses the active site and allosteric regulatory sites, and a β2 subunit that houses the tyrosyl-diiron radical cofactor. Ribonucleotide reduction requires that both subunits form a compact α2 β2 state allowing for radical transfer from β2 to α2 RNR activity is regulated allosterically by dATP, which inhibits RNR, and by ATP, which restores activity...
April 26, 2018: Journal of Biological Chemistry
Chao Li, Jingfang Zheng, Si Chen, Bin Huang, Guosheng Li, Zichao Feng, Jiwei Wang, Shujun Xu
Glioblastoma pathogenesis is related to multiple processes that affected by dozens of regulatory factors, but the potential underlying factors regulating glioblastoma progression remains unclear. The goal of this research was to determine how the ribonucleotide reductase M2 subunit (RRM2) influenced proliferation, invasion, migration, and apoptosis of human glioblastoma cells. The level of proliferation of human glioblastoma cells was measured through CCK8, colony formation assay and immunofluorescence stains...
April 18, 2018: Journal of Cellular Physiology
Hannah Rose, Manas Ghosh, Ailiena Maggiolo, Christopher J Pollock, Elizabeth J Blaesi, Viviane Hajj, Yifeng Wei, Lauren J Rajakovich, Wei-Chen Chang, Yilin Han, Mariana Hajj, Carsten Krebs, Alexey Silakov, Maria-Eirini Pandelia, J Martin Bollinger, Amie K Boal
A ribonucleotide reductase (RNR) from Flavobacterium johnsoniae (Fj) differs fundamentally from known (subclass a-c) class I RNRs, warranting its assignment to a new subclass, Id. Its β subunit shares with Ib counterparts the requirements for manganese(II) and superoxide for activation, but it does not require the superoxide-supplying flavoprotein (NrdI) needed in Ib systems, instead scavenging the oxidant from solution. Although Fj β has tyrosine at the appropriate sequence position (Tyr 104), this residue is not oxidized to a radical upon activation, as occurs in the Ia/b proteins...
April 2, 2018: Biochemistry
Colin G Miller, Arne Holmgren, Elias S J Arnér, Edward E Schmidt
Over the past seven decades, research on autotrophic and heterotrophic model organisms has defined how the flow of electrons ("reducing power") from high-energy inorganic sources, through biological systems, to low-energy inorganic products like water, powers all of Life's processes. Universally, an initial major biological recipient of these electrons is nicotinamide adenine dinucleotide-phosphate, which thereby transits from an oxidized state (NADP+ ) to a reduced state (NADPH). A portion of this reducing power is then distributed via the cellular NADPH-dependent disulfide reductase systems as sequential reductions of disulfide bonds...
March 30, 2018: Free Radical Biology & Medicine
Yury O Nunez Lopez, Maria Laura Messi, Richard E Pratley, Tan Zhang, Osvaldo Delbono
We recently reported that in addition to its classical cytoplasmic location, the fast skeletal muscle Troponin T3 (TnT3) shuttles to the nucleus, where it appears to perform nonclassical transcription regulatory functions. Importantly, changes in the composition of the nucleus-localized pool of TnT3 and its fragments contribute to age-dependent muscle damage and wasting. Here, using ChIP-Seq, we demonstrate that TnT3 associates with DNA consensus sequences including the TGCCT motif, which is required for p53 binding to the promoter area of p53-related genes...
March 26, 2018: Experimental Gerontology
Christopher R Chitambar, Mona M Al-Gizawiy, Hisham S Alhajala, Kimberly R Pechman, Janine P Wereley, Robert Wujek, Paul A Clark, John S Kuo, William E Antholine, Kathleen M Schmainda
Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMECs) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSCs) lines express TfRs and that their growth is inhibited by gallium maltolate (GaM) in vitro...
March 28, 2018: Molecular Cancer Therapeutics
Toshinori Ozaki, Meng Yu, Danjing Yin, Dan Sun, Yuyan Zhu, Youquan Bu, Meixiang Sang
BACKGROUND: Despite the remarkable advances in the early diagnosis and treatment, overall 5-year survival rate of patients with pancreatic cancer is less than 10%. Gemcitabine (GEM), a cytidine nucleoside analogue and ribonucleotide reductase inhibitor, is a primary option for patients with advanced pancreatic cancer; however, its clinical efficacy is extremely limited. This unfavorable clinical outcome of pancreatic cancer patients is at least in part attributable to their poor response to anti-cancer drugs such as GEM...
March 20, 2018: BMC Cancer
Nan Wang, Yong Li, Jianhong Zhou
Ribonucleotide reductase subunit M2 (RRM2) is associated with the biological behaviours of cancers, including apoptosis, cell proliferation, invasion, cell cycle and migration. Previous studies have suggested that the expression of RRM2 plays critical roles in tumorigenesis in several cancer types. However, the precise molecular mechanism remains unknown. We previously identified RRM2 as a novel downstream target that is activated by human papillomavirus E7, which activates the extracellular signal-regulated kinase 1/2 signalling pathway, but further studies are warranted to establish RRM2 as a therapeutic target...
March 2018: Oncology Letters
Yuan-Liang Zhang, Jie-Wen Sun, Yin-Yin Xie, Yan Zhou, Ping Liu, Jia-Chun Song, Chun-Hui Xu, Lan Wang, Dan Liu, Ai-Ning Xu, Zhu Chen, Sai-Juan Chen, Xiao-Jian Sun, Qiu-Hua Huang
The histone H3 lysine 36 methyltransferase SETD2 is frequently mutated in various cancers, including leukemia. However, there has not been any functional model to show the contribution of SETD2 in hematopoiesis or the causal role of SETD2 mutation in tumorigenesis. In this study, using a conditional Setd2 knockout mouse model, we show that Setd2 deficiency skews hematopoietic differentiation and reduces the number of multipotent progenitors; although the number of phenotypic hematopoietic stem cells (HSCs) in Setd2-deleted mice is unchanged, functional assays, including serial BM transplantation, reveal that the self-renewal and competitiveness of HSCs are impaired...
April 2018: Cell Research
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