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https://www.readbyqxmd.com/read/28700353/chiral-platinum-ii-4-2-3-dihydroxypropyl-formamide-oxo-aporphine-foa-complexes-promote-tumor-cells-apoptosis-by-directly-targeting-g-quadruplex-dna-in-vitro-and-in-vivo
#1
Qi-Pin Qin, Jiao-Lan Qin, Ming Chen, Yu-Lan Li, Ting Meng, Jie Zhou, Hong Liang, Zhen-Feng Chen
Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(-)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698207/strict-tropism-for-cd71-cd234-human-reticulocytes-limits-plasmodium-cynomolgi-s-zoonotic-potential
#2
Varakorn Kosaisavee, Rossarin Suwanarusk, Adeline C Y Chua, Dennis E Kyle, Benoit Malleret, Rou Zhang, Mallika Imwong, Rawiwan Imerbsin, Ratawan Ubalee, Hugo Sámano-Sánchez, Bryan K S Yeung, Jessica Ong, Eric Lombardini, François Nosten, Kevin S W Tan, Pablo Bifani, Georges Snounou, Laurent Rénia, Bruce Russell
Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P. cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date only a single case of naturally acquired P. cynomolgi has been found in humans. In this study we show that whereas P. cynomolgi merozoites invade monkey red blood cells (RBCs) indiscriminately in vitro, for humans they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234)...
July 11, 2017: Blood
https://www.readbyqxmd.com/read/28667246/genetic-profile-and-biological-implication-of-pin2-trf1-interacting-telomerase-inhibitor-1-pinx1-in-human-cancers-an-analysis-using-the-cancer-genome-atlas
#3
Wei-Juan Huang, Mei Li, Xiao-Han Jin, Xiao-Jia Huang, Wei Zhao, Xiao-Peng Tian
Pin2/TRF1-interacting telomere inhibitor 1 (PinX1) was originally identified as a telomerase inhibitor, involved in maintaining telomerase activity, telomere length, and chromosomal stability. However, research has shown that PinX1 can have opposing molecular status in its expression patterns in several other tumor types. We thus investigated the genetic profile and biological implication of PinX1 in several human cancers using the cBioportal database. Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma...
June 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28659816/cardioprotective-effects-of-sirt6-in-a-mouse-model-of-transverse-aortic-constriction-induced-heart-failure
#4
Yongming Li, Xianda Meng, Wenguang Wang, Fu Liu, Zhiru Hao, Yang Yang, Jinbo Zhao, Wensi Yin, Lijuan Xu, Ruiping Zhao, Jiang Hu
SIRT6, a member of the NAD (+)-dependent class III deacetylase sirtuin family, plays important roles in the maintenance of cardiovascular homeostasis. Telomere shortening is a risk factor for age-associated diseases, including heart disease. In the present study, we investigated the role of SIRT6 and telomerase in a mouse model of transverse aortic constriction (TAC)-induced heart failure. SIRT6, telomerase reverse transcriptase (TERT), and telomere repeat binding factor (TRF)-1 were significantly downregulated in TAC mice compared with their expression in sham-operated mice...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28657713/association-of-a-platinum-complex-to-a-g-quadruplex-ligand-enhances-the-telomere-disruption
#5
Razan Charif, Christine Granotier-Beckers, Hélène Charlotte Bertrand, Joel Poupon, Evelyne Segal-Bendirdjian, Marie-Paule Teulade-Fichou, François D Boussin, Sophie Bombard
Telomeres protect the end of chromosomes against illegitimate recombination and repair. They can be targets for G-quadruplex ligands and platinum complexes due to their repeated G-rich sequences. Protection of telomeres is ensured by a complex of six proteins, including TRF2, which inhibits the DNA damage response pathway. We analyzed telomere modifications induced in cancer cells by the experimental hybrid platinum complex, Pt-MPQ, comprising both an ethylene diamine monofunctional platinum complex and a G-quadruplex recognition moiety (MPQ)...
June 28, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28633355/how-proteins-bind-to-dna-target-discrimination-and-dynamic-sequence-search-by-the-telomeric-protein-trf1
#6
Milosz Wieczór, Jacek Czub
Target search as performed by DNA-binding proteins is a complex process, in which multiple factors contribute to both thermodynamic discrimination of the target sequence from overwhelmingly abundant off-target sites and kinetic acceleration of dynamic sequence interrogation. TRF1, the protein that binds to telomeric tandem repeats, faces an intriguing variant of the search problem where target sites are clustered within short fragments of chromosomal DNA. In this study, we use extensive (>0.5 ms in total) MD simulations to study the dynamical aspects of sequence-specific binding of TRF1 at both telomeric and non-cognate DNA...
June 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28434530/accelerated-cellular-senescence-as-underlying-mechanism-for-functionally-impaired-bone-marrow-derived-progenitor-cells-in-ischemic-heart-disease
#7
Evelien Nollet, Vicky Y Hoymans, Inez R Rodrigus, Dina De Bock, Marc Dom, Viviane O M Van Hoof, Christiaan J Vrints, Emeline M Van Craenenbroeck
BACKGROUND AND AIMS: Bone marrow (BM)-derived progenitor cells are functionally impaired in patients with ischemic heart disease (IHD), thereby hampering the outcome of autologous stem cell therapy. In search for underlying mechanisms for this BM dysfunction, accelerated cellular senescence was explored. METHODS: We analysed telomere length of BM-derived mononuclear cells (MNC) by MMqPCR in patients with coronary artery disease (n = 12), ischemic heart failure (HF; n = 9), non-ischemic HF (n = 7) and controls (n = 10), and related it to their myeloid differentiation capacity...
May 2017: Atherosclerosis
https://www.readbyqxmd.com/read/28424414/integrated-analysis-of-promoter-methylation-and-expression-of-telomere-related-genes-in-breast-cancer
#8
Jianfu Heng, Fan Zhang, Xinwu Guo, Lili Tang, Limin Peng, Xipeng Luo, Xunxun Xu, Shouman Wang, Lizhong Dai, Jun Wang
Telomeres at the ends of eukaryotic chromosomes play a critical role in tumorgenesis. Using microfluidic PCR and next-generation bisulfite sequencing technology, we investigated the promoter methylation of 29 telomere related genes in paired tumor and normal tissues from 184 breast cancer patients. The expression of significantly differentially methylated genes was quantified using qPCR method.We observed that the average methylation level of the 29 telomere related genes was significant higher in tumor than that in normal tissues (P = 4...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28417530/rho-gdp-dissociation-inhibitor-%C3%AE-is-a-potential-prognostic-biomarker-and-controls-telomere-regulation-in-colorectal-cancer
#9
Dandan Huang, Weisi Lu, Shaomin Zou, Huaiming Wang, Yuanling Jiang, Xiya Zhang, Pengqing Li, Zhou Songyang, Lei Wang, Jianping Wang, Junjiu Huang, Lekun Fang
Rho GDP-dissociation inhibitor α (RhoGDIα) is an essential regulator for Rho GTPases. Although RhoGDIα may serve as an oncogene in colorectal cancer (CRC), the underlying mechanism is still unclear. We investigated the function, mechanism, and clinical significance of RhoGDIα in CRC progression. We founded that downregulation of RhoGDIα repressed CRC cell proliferation, motility, and invasion. Overexpression of RhoGDIα increased DNA damage response signals at telomeres, and led to telomere shortening in CRC cells, also being validated in 26 pairs of CRC tissues...
July 2017: Cancer Science
https://www.readbyqxmd.com/read/28404540/abnormal-mrna-expression-levels-of-telomere-binding-proteins-represent-biomarkers-in-myelodysplastic-syndromes-a-case-control-study
#10
Baoshan Liu, Rongdi Yan, Jie Zhang, Bin Wang, Hu Sun, Xing Cui
OBJECTIVE: As the abnormal shortening of telomeres has been shown in myelodysplastic syndromes (MDS) patients, this study was to find the relationship between the mRNA expression levels of telomere-binding proteins(TRF1/TRF2/TIN2/TPP1/POT1/RAP1) and the risk in MDS. MATERIALS AND METHODS: A total of 40 patients with MDS and 40 normal controls were selected for the study. Using telomere content assays and quantitative reverse transcription-polymerase chain reaction, we examined the mRNA levels of telomere-binding proteins TRF1/TRF2/TIN2/TPP1/POT1/RAP1 in patients with MDS...
April 13, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/28381412/the-ddr-at-telomeres-lacking-intact-shelterin-does-not-require-substantial-chromatin-decompaction
#11
Leonid A Timashev, Hazen Babcock, Xiaowei Zhuang, Titia de Lange
Telomeres are protected by shelterin, a six-subunit protein complex that represses the DNA damage response (DDR) at chromosome ends. Extensive data suggest that TRF2 in shelterin remodels telomeres into the t-loop structure, thereby hiding telomere ends from double-stranded break repair and ATM signaling, whereas POT1 represses ATR signaling by excluding RPA. An alternative protection mechanism was suggested recently by which shelterin subunits TRF1, TRF2, and TIN2 mediate telomeric chromatin compaction, which was proposed to minimize access of DDR factors...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28381410/the-telomeric-dna-damage-response-occurs-in-the-absence-of-chromatin-decompaction
#12
Aleksandra Vancevska, Kyle M Douglass, Verena Pfeiffer, Suliana Manley, Joachim Lingner
Telomeres are specialized nucleoprotein structures that protect chromosome ends from DNA damage response (DDR) and DNA rearrangements. The telomeric shelterin protein TRF2 suppresses the DDR, and this function has been attributed to its abilities to trigger t-loop formation or prevent massive decompaction and loss of density of telomeric chromatin. Here, we applied stochastic optical reconstruction microscopy (STORM) to measure the sizes and shapes of functional human telomeres of different lengths and dysfunctional telomeres that elicit a DDR...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28324506/induction-of-site-specific-oxidative-damage-at-telomeres-by-killerred-fused-shelretin-proteins
#13
Rong Tan, Li Lan
Chronic oxidative stress is the major endogenous metabolic stress and contributes directly to telomere shortening and senescence. Understanding the dysfunction of telomeres under oxidative stress will greatly facilitate healthy aging and advance the treatment of aging-related diseases. Here, we describe the KR-TEL (KillerRed induced DNA damage at telomeres) system that induces site-specific oxidative damage at telomeres. We have developed the KR-TEL system by fusing killerred with the shelterin component TRF1 (KR-TRF1) or other shelterin proteins...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28273089/drosophila-trf2-and-taf9-regulate-lipid-droplet-size-and-phospholipid-fatty-acid-composition
#14
Wei Fan, Sin Man Lam, Jingxue Xin, Xiao Yang, Zhonghua Liu, Yuan Liu, Yong Wang, Guanghou Shui, Xun Huang
The general transcription factor TBP (TATA-box binding protein) and its associated factors (TAFs) together form the TFIID complex, which directs transcription initiation. Through RNAi and mutant analysis, we identified a specific TBP family protein, TRF2, and a set of TAFs that regulate lipid droplet (LD) size in the Drosophila larval fat body. Among the three Drosophila TBP genes, trf2, tbp and trf1, only loss of function of trf2 results in increased LD size. Moreover, TRF2 and TAF9 regulate fatty acid composition of several classes of phospholipids...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28216227/nek7-protects-telomeres-from-oxidative-dna-damage-by-phosphorylation-and-stabilization-of-trf1
#15
Rong Tan, Satoshi Nakajima, Qun Wang, Hongxiang Sun, Jing Xue, Jian Wu, Sabine Hellwig, Xuemei Zeng, Nathan A Yates, Thomas E Smithgall, Ming Lei, Yu Jiang, Arthur S Levine, Bing Su, Li Lan
Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28166612/acute-exercise-activates-p38-mapk-and-increases-the-expression-of-telomere-protective-genes-in-cardiac-muscle
#16
Andrew T Ludlow, Laila Gratidão, Lindsay W Ludlow, Espen E Spangenburg, Stephen M Roth
What is the central question of this study? A positive association between telomere length and exercise training has been shown in cardiac tissue of mice. It is currently unknown how each bout of exercise influences telomere-length-regulating proteins. We sought to determine how a bout of exercise altered the expression of telomere-length-regulating genes and a related signalling pathway in cardiac tissue of mice. What is the main finding and its importance? Acute exercise altered the expression of telomere-length-regulating genes in cardiac tissue and might be related to altered mitogen-activated protein kinase signalling...
April 1, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28162998/common-telomere-changes-during-in%C3%A2-vivo-reprogramming-and-early-stages-of-tumorigenesis
#17
Rosa M Marión, Isabel López de Silanes, Lluc Mosteiro, Benjamin Gamache, María Abad, Carmen Guerra, Diego Megías, Manuel Serrano, Maria A Blasco
Reprogramming of differentiated cells into induced pluripotent stem cells has been recently achieved in vivo in mice. Telomeres are essential for chromosomal stability and determine organismal life span as well as cancer growth. Here, we study whether tissue dedifferentiation induced by in vivo reprogramming involves changes at telomeres. We find telomerase-dependent telomere elongation in the reprogrammed areas. Notably, we found highly upregulated expression of the TRF1 telomere protein in the reprogrammed areas, which was independent of telomere length...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28160604/tankyrase1-mediated-poly-adp-ribosyl-ation-of-trf1-maintains-cell-survival-after-telomeric-dna-damage
#18
Lu Yang, Luxi Sun, Yaqun Teng, Hao Chen, Ying Gao, Arthur S Levine, Satoshi Nakajima, Li Lan
Oxidative DNA damage triggers telomere erosion and cellular senescence. However, how repair is initiated at telomeres is largely unknown. Here, we found unlike PARP1-mediated Poly-ADP-Ribosylation (PARylation) at genomic damage sites, PARylation at telomeres is mainly dependent on tankyrase1 (TNKS1). TNKS1 is recruited to damaged telomeres via its interaction with TRF1, which subsequently facilitates the PARylation of TRF1 after damage. TNKS inhibition abolishes the recruitment of the repair proteins XRCC1 and polymerase β at damaged telomeres, while the PARP1/2 inhibitor only has such an effect at non-telomeric damage sites...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28158503/wrn-is-recruited-to-damaged-telomeres-via-its-rqc-domain-and-tankyrase1-mediated-poly-adp-ribosylation-of-trf1
#19
Luxi Sun, Satoshi Nakajima, Yaqun Teng, Hao Chen, Lu Yang, Xiukai Chen, Boya Gao, Arthur S Levine, Li Lan
Werner syndrome (WS) is a progeroid-like syndrome caused by WRN gene mutations. WS cells exhibit shorter telomere length compared to normal cells, but it is not fully understood how WRN deficiency leads directly to telomere dysfunction. By generating localized telomere-specific DNA damage in a real-time fashion and a dose-dependent manner, we found that the damage response of WRN at telomeres relies on its RQC domain, which is different from the canonical damage response at genomic sites via its HRDC domain...
April 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28123587/analysis-of-molecular-markers-as-predictive-factors-of-lymph-node-involvement-in-breast-carcinoma
#20
Luciana Marques Paula, Luis Henrique Ferreira De Moraes, Abaeté Leite Do Canto, Laurita Dos Santos, Airton Abrahão Martin, Silvia Regina Rogatto, Renata De Azevedo Canevari
Nodal status is the most significant independent prognostic factor in breast cancer. Identification of molecular markers would allow stratification of patients who require surgical assessment of lymph nodes from the large numbers of patients for whom this surgical procedure is unnecessary, thus leading to a more accurate prognosis. However, up to now, the reported studies are preliminary and controversial, and although hundreds of markers have been assessed, few of them have been used in clinical practice for treatment or prognosis in breast cancer...
January 2017: Oncology Letters
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