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https://www.readbyqxmd.com/read/28265066/resistance-mechanisms-to-tp53-mdm2-inhibition-identified-by-in-vivo-piggybac-transposon-mutagenesis-screen-in-an-arf-mouse-model
#1
Emilie A Chapeau, Agnieszka Gembarska, Eric Y Durand, Emeline Mandon, Claire Estadieu, Vincent Romanet, Marion Wiesmann, Ralph Tiedt, Joseph Lehar, Antoine de Weck, Roland Rad, Louise Barys, Sebastien Jeay, Stephane Ferretti, Audrey Kauffmann, Esther Sutter, Armelle Grevot, Pierre Moulin, Masato Murakami, William R Sellers, Francesco Hofmann, Michael Rugaard Jensen
Inhibitors of double minute 2 protein (MDM2)-tumor protein 53 (TP53) interaction are predicted to be effective in tumors in which the TP53 gene is wild type, by preventing TP53 protein degradation. One such setting is represented by the frequent CDKN2A deletion in human cancer that, through inactivation of p14ARF, activates MDM2 protein, which in turn degrades TP53 tumor suppressor. Here we used piggyBac (PB) transposon insertional mutagenesis to anticipate resistance mechanisms occurring during treatment with the MDM2-TP53 inhibitor HDM201...
March 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28193319/a-conformational-switch-regulates-the-ubiquitin-ligase-huwe1
#2
Bodo Sander, Wenshan Xu, Martin Eilers, Nikita Popov, Sonja Lorenz
The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly...
February 14, 2017: ELife
https://www.readbyqxmd.com/read/28185908/purification-and-biophysical-characterization-of-the-aimp2-dx2-protein
#3
Roshan Jha, Hye Young Cho, Ameeq Ul Mushtaq, Kiho Lee, Dae Gyu Kim, Sunghoon Kim, Young Ho Jeon
Besides their primary role in protein synthesis, aminoacyl-tRNA synthetases (AARSs) are involved in several non-canonical processes such as apoptosis, inflammation and angiogenesis through their interactions with various cellular proteins. Nine of these AARSs interact with three aminoacyl-tRNA synthetase interacting multifunctional proteins (AIMPs), forming a multi-synthetase complex (MSC) in eukaryotes. Among the three AIMPs, AIMP2 is involved in controlling cell proliferation and apoptosis. However, a splicing variant of AIMP2 lacking exon 2, referred to as AIMP2-DX2, is oncogenic and compromises the pro-apoptotic activity of AIMP2 by competing with it for p53 and TRAF2...
February 7, 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28150872/polymorphism-in-anril-is-associated-with-relapse-in-patients-with-multiple-myeloma-after-autologous-stem-cell-transplant
#4
Ming J Poi, Junan Li, Douglas W Sborov, Zachary VanGundy, Yu Kyoung Cho, Misty Lamprecht, Flavia Pichiorri, Mitch A Phelps, Craig C Hofmeister
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and overproduction of monoclonal immunoglobins. Treatment with melphalan is currently standard of care for younger and fit patients when followed by hematopoietic stem cell transplantation (HSCT), and in transplant ineligible patients when used in combination regimens. It has been previously shown that changes in the p53 pathway are associated with melphalan efficacy, but the regulatory role of the p14ARF-MDM2-p53 axis has yet to be fully explored...
February 2, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28068434/annexin-s100a-protein-family-regulation-through-p14arf-p53-activation-a-role-in-cell-survival-and-predicting-treatment-outcomes-in-breast-cancer
#5
Diana Hatoum, Daniel Yagoub, Alireza Ahadi, Najah T Nassif, Eileen M McGowan
The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy...
2017: PloS One
https://www.readbyqxmd.com/read/27997910/effects-of-cdkn2a-p16ink4a-p14arf-over-expression-on-proliferation-and-migration-of-human-melanoma-a375-cells
#6
Ming Bai, Nan-Ze Yu, Fei Long, Cheng Feng, Xiao-Jun Wang
OBJECTIVE: This study aims to investigate the effects of CDKN2A (p16INK4A/p14ARF) over-expression on the proliferation and migration of human melanoma A375 cells. METHODS: Melanoma tissues and pigmented nevi tissues were collected. Human melanoma A375 cells were transfected by CDKN2A (p16INK4A) and CDKN2A (p14ARF) over-expressing vectors and then assigned into blank, negative control (NC), p16INK4A and p14ARF groups. The expression of CDKN2A (p16INK4A) and CDKN2A (p14ARF) mRNA and protein was detected by qRT-PCR and Western blotting...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27965321/suppressing-p16ink4a-and-p14arf-pathways-overcomes-apoptosis-in-individualized-human-embryonic-stem-cells
#7
Wenqian Wang, Yanling Zhu, Ke Huang, Yongli Shan, Juan Du, Xiaoya Dong, Ping Ma, Penafei Wu, Jian Zhang, Wenhao Huang, Tian Zhang, Baojian Liao, Deyang Yao, Guangjin Pan, Jiajun Liu
Dissociation-induced apoptosis is a striking phenomenon in human embryonic stem cells (hESCs), but not in naïve mouse ESCs. Rho-associated kinase-dependent actin-myosin hyperactivation is an underlying mechanism that triggers apoptosis in dissociated hESCs; however, in this study, we show that the Ink4A-ARF-mediated senescence pathway is another mechanism to cause apoptosis in individualized hESCs. We show that P16(INK4A) and P14(ARF) are immediately induced in hESCs upon dissociation, but not in mouse ESCs...
December 13, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27814275/detection-of-bladder-cancer-in-urine-sediments-by-a-hypermethylation-panel-of-selected-tumor-suppressor-genes
#8
Michaƚ Pietrusiński, Ƚukasz Kȩpczyński, Adam Jȩdrzejczyk, Edyta Borkowska, Magdalena Traczyk-Borszyńska, Maria Constantinou, Bogdan Kaƚużewski, Maciej Borowiec
BACKGROUND: Promoter hypermethylation can be a useful biomarker for early detection and prognosis of bladder cancer, monitoring response to treatment and complement classical diagnostic procedures. OBJECTIVE: The molecular test was performed on DNA from bladder cancer cells in voided urine samples, tumor tissue DNA and normal control DNAs. We aimed to assess the diagnostic potential of epigenetic changes in urine DNA from bladder cancer cases at various clinico-pathological stages of the disease...
2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/27793846/molecular-chaperone-hsp90-is-necessary-to-prevent-cellular-senescence-via-lysosomal-degradation-of-p14arf
#9
Su Yeon Han, Aram Ko, Haruhisa Kitano, Chel Hun Choi, Min-Sik Lee, Jinho Seo, Junya Fukuoka, Soo-Youl Kim, Stephen M Hewitt, Joon-Yong Chung, Jaewhan Song
The tumor suppressor function of p14ARF is regulated at a posttranslational level via mechanisms yet to be fully understood. Here, we report the identification of an unconventional p14ARF degradation pathway induced by the chaperone HSP90 in association with the E3 ubiquitin ligase C-terminus of HSP70-interacting protein (CHIP). The ternary complex of HSP90, CHIP, and p14ARF was required to induce the lysosomal degradation of p14ARF by an ubiquitination-independent but LAMP2A-dependent mechanism. Depletion of HSP90 or CHIP induced p14ARF-dependent senescence in human fibroblasts...
January 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/27507052/long-non-coding-rna-anril-promotes-the-invasion-and-metastasis-of-thyroid-cancer-cells-through-tgf-%C3%AE-smad-signaling-pathway
#10
Jian-Jie Zhao, Shuai Hao, Ling-Li Wang, Chun-Yan Hu, Shu Zhang, Ling-Ji Guo, Gang Zhang, Bo Gao, Yan Jiang, Wu-Guo Tian, Dong-Lin Luo
OBJECTIVE: To investigate the effect of antisense non-coding RNA in the INK4 locus (ANRIL) on invasion and metastasis of thyroid cancer (TC). RESULTS: ANRIL expression was significantly up-regulated in TC tissues and cells (P < 0.001), and ANRIL expression was significantly different regarding histological grade and LNM (both P < 0.01). The siRNA-mediated ANRIL silencing inhibits proliferation, invasion, and metastasis of TPC-1 and SW579 cells, and lung metastasis, which can be reversed by TGF-β1 siRNA...
September 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27436753/k259-sumoylation-of-dgcr8-promoted-by-p14arf-exerts-a-tumor-suppressive-function
#11
Changhong Zhu, Cheng Chen, Ran Chen, Rong Deng, Xian Zhao, Hailong Zhang, Jinzhuo Duo, Qin Chen, Hui Jin, Yanli Wang, Jian Huang, Ming Xu, Jianxiu Yu
No abstract text is available yet for this article.
July 19, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27414035/genetic-variants-in-the-p14arf-mdm2-tp53-pathway-are-associated-with-the-prognosis-of-esophageal-squamous-cell-carcinoma-patients-treated-with-radical-resection
#12
Jing Li, Yang Tang, Liu Huang, Qianqian Yu, Guangyuan Hu, Xianglin Yuan
The p14ARF/MDM2/ TP53 pathway is known to play an important role in tumor progression by cell cycle control, although the association between this pathway and the prognosis of esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we explored the association between genetic variants in the p14ARF/MDM2/TP53 pathway and prognosis in ESCC patients with radical resection. 124 ESCC patients with radical resection were included in this retrospective study and genotyped using the MassArray method. According to multivariate Cox hazard analysis and multiple testing, the TC/CC genotype of p14ARF rs3814960 was shown to be strongly related to a decreased overall survival (OS) (HR = 2...
2016: PloS One
https://www.readbyqxmd.com/read/27356775/the-9p21-locus-and-its-potential-role-in-atherosclerosis-susceptibility-molecular-mechanisms-and-clinical-implications
#13
Amir Tajbakhsh, Seyed Mahdi Hassanian, Mohammad Sadegh Khorrami, Alireza Pasdar, Ehsan Tabatabai, Seyed Mohammad Reza Parizadeh, Mostafa Fazeli, Sharareh Gholamin, Gordon A Ferns, Majid Ghayour-Mobarhan, Amir Avan
Cardiovascular disease (CVD) is the leading cause of global mortality. Although extensive efforts have been made to identify valid biomarkers for CVD risk, relatively ¬¬¬few are of proven clinical utility. It is recognized that genetic factors play a major role in determining the susceptibility to CVD. Recent genome-wide-association-studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CVD. Several genetic-polymorphisms have been identified in this region that are highly associated with CVD, and these are clustered around the gene loci for CDKN2B (coding for p15ink4b), CDKN2A (coding for p16ink4a and p14ARF) and the 3' end of CDKN2BAS, which has been termed antisense noncoding RNA in the INK4 locus (ANRIL)...
June 27, 2016: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27356744/mmp7-interacts-with-arf-in-nucleus-to-potentiate-tumor-microenvironments-for-prostate-cancer-progression-in-vivo
#14
Yingqiu Xie, Wenfu Lu, Shenji Liu, Qing Yang, J Shawn Goodwin, Sandeep Anantha Sathyanarayana, Siddharth Pratap, Zhenbang Chen
ARF couples with TP53 in a canonical signaling pathway to activate cellular senescence for tumor suppressive function under oncogenic insults. However, the mechanisms on aberrant elevation of ARF in cancers are still poorly understood. We previously showed that ARF (p14ARF in human and p19Arf in mouse) elevation correlates with PTEN loss and stabilizes SLUG to reduce cell adhesion in prostate cancer (PCa). Here we report that ARF is essential for MMP7 expression, E-Cadherin decrease and the anchorage loss to the extracellular matrix (ECM) in PCa in vitro and in vivo...
July 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27323397/gltscr2-promotes-the-nucleoplasmic-translocation-and-subsequent-degradation-of-nucleolar-arf
#15
Sun Lee, Young-Eun Cho, Sang-Hoon Kim, Yong-Jun Kim, Jae-Hoon Park
The alternative reading frame protein (p14ARF/ARF) is a key determinant of cell fate, acting as a potent tumor suppressor through a p53/MDM2-dependent pathway or promoting apoptosis in a p53-independent manner. The ARF protein is mainly expressed in the nucleolus and sequestered by nucleophosmin (NPM), whereas ARF-binding proteins, including p53 and MDM2, predominantly reside in the nucleoplasm. This raises the question of how nucleolar ARF binds nucleoplasmic signaling proteins to suppress tumor growth or inhibit cell cycle progression...
June 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27156320/improved-noninvasive-bladder-cancer-diagnosis-using-urine-sediments-and-novel-dna-methylation-biomarker-panels
#16
Kaichen Wang, Yudan Tian, Hongmei Xu
BACKGROUND: Aberrant DNA methylation status early in carcinogenesis represents a potential indicator of tumor detection. We would like to establish a DNA methylation biomarker panel for bladder cancer detection in the research. METHODS: Seven candidate genes with known cancer associations were selected for this study. The DNA methylation status of the candidate genes was analyzed by methylation-specific polymerase chain reaction assays to evaluate the relationship between bladder cancer and target gene methylation status in the urine sediments of participants...
2016: Clinical Laboratory
https://www.readbyqxmd.com/read/26999279/relationships-between-p14arf-gene-methylation-and-clinicopathological-features-of-colorectal-cancer-a-meta-analysis
#17
Zhangjian Zhou, Hao Zhang, Jianguo Lai, Dongmei Diao, Wenhan Li, Chengxue Dang, Yongchun Song
We conducted a meta-analysis to explore the relationships between p14ARF gene methylation and clinicopathological features of colorectal cancer (CRC). Databases, including Pubmed, Embase and Cochrane Library, were searched and, finally, a total of 18 eligible researches encompassing 1988 CRC patients were selected. Combined odds ratios (ORs) with 95% confidence intervals (95% CIs) were evaluated under a fixed effects model for absence of heterogeneity. Significant associations were observed between p14ARF gene methylation and tumor location (OR = 2...
2016: PloS One
https://www.readbyqxmd.com/read/26985633/cmyc-p53-feedback-mechanism-regulates-the-dynamics-of-t-lymphocytes-in-the-immune-response
#18
Harsha S Madapura, Daniel Salamon, Klas G Wiman, Sonia Lain, Eva Klein, Noémi Nagy
Activation and proliferation of T cells are tightly regulated during the immune response. We show here that kinetics of proliferation of PHA activated T cells follows the expression of cMyc. Expression of p53 is also elevated and remains high several days after activation. To investigate the role of p53 in activated T cells, its expression was further elevated with nultin-3 treatment, a small molecule that dissociates the E3 ubiquitin protein ligase MDM2 from p53. Concomitantly, cMyc expression and proliferation decreased...
May 2, 2016: Cell Cycle
https://www.readbyqxmd.com/read/26815194/-p14arf-enhances-cisplatin-induced-apoptosis-in-human-osteosarcoma-cells-in-p53-independent-pathway
#19
Xiufang Huang, Xiangwei Yuan, Zhongxian Chen, Shenggen Liang
OBJECTIVE: To study effect of tumor suppressor p14ARF on cisplatin-induced apoptosis in human osteosarcoma cells with its molecular mechanisms to provide evidences for increasing chemosensitivity of osteosarcoma. METHODS: pcDNA3.1-p14ARF plasmid was stable transfected into MG63 cells lack of p14ARF expression. Expression of p14ARF on mRNA and protein level was evaluated with RT-PCR and Western blot. MG63, MG63-vec and MG63-ARF cells were treated with cisplatin. Cell growth inhibition and IC50 were determined through MTT assay...
September 15, 2015: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/26686095/nuclear-trafficking-of-egfr-by-vps34-represses-arf-expression-to-promote-lung-tumor-cell-survival
#20
D Dayde, M Guerard, P Perron, A-S Hatat, C Barrial, B Eymin, S Gazzeri
Epidermal growth factor receptor (EGFR) is a cell surface receptor that has an essential role in cell proliferation and survival, and overexpression of EGFR is a common feature of human cancers. In Non-small-cell lung cancer (NSCLC), activating mutations of EGFR have also been described. We recently showed that mutant EGFR-L858R inhibits the expression of the p14ARF tumor-suppressor protein to promote cell survival. In this study, we defined the molecular bases by which EGFR controls Arf expression. Using various lung tumor models, we showed that EGF stimulation inhibits Arf transcription by a mechanism involving the nuclear transport and recruitment of EGFR to the Arf promoter...
July 28, 2016: Oncogene
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