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https://www.readbyqxmd.com/read/29340077/lrp6-targeting-suppresses-gastric-tumorigenesis-via-p14arf-mdm2-p53-dependent-cellular-senescence
#1
Haibin Wang, Guoxing Xu, Zhengjie Huang, Weizheng Li, Huali Cai, Yunda Zhang, Disheng Xiong, Gang Liu, Shengjie Wang, Zengfu Xue, Qi Luo
NLRP6, a member of the Nod-like receptor family, protects against chemically induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms involved in this NLRP6-mediated protection remain unclear. Here, we show that NLRP6 was down-regulated in approximately 75% of primary gastric cancer cases and exhibited significant associations with advanced clinical-stage lymph node metastasis and poor overall survival. Functional studies established that ectopic overexpression or down-regulation of NLRP6 inhibited cancer cell proliferation by inducing cell cycle arrest at the G1 phase via P21 and Cyclin D1 both in vitro and in vivo...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29283500/identification-of-a-novel-nucleophosmin-interaction-motif-in-the-tumor-suppressor-p14arf
#2
Enrico Luchinat, Sara Chiarella, Mimma Franceschini, Adele Di Matteo, Maurizio Brunori, Lucia Banci, Luca Federici
The tumor suppressor p14arf interacts, in response to oncogenic signals, with the p53 E3-ubiquitin ligase HDM2, thereby resulting in p53 stabilization and activation. In addition, it also exerts tumor suppressive functions in p53-independent contexts. The activities of p14arf are regulated by the nucleolar chaperone nucleophosmin (NPM1), which controls its levels and cellular localization. In acute myeloid leukemia with mutations in the NPM1 gene, mutated NPM1 aberrantly translocates in the cytosol carrying with itself p14arf that is subsequently degraded, thus impairing the p14arf-HDM2-p53 axis...
December 28, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29240242/the-9p21-locus-a-potential-therapeutic-target-and-prognostic-marker-in-breast-cancer
#3
REVIEW
Mahdi Rivand, Mohammad-Sadegh Khorrami, Hamid Fiuji, Soodabeh Shahidsales, Malihe Hasanzadeh, Mir Hadi Jazayeri, Seyed Mahdi Hassanian, Gordon A Ferns, Nafiseh Saghafi, Amir Avan
Breast cancer is an important cause of cancer related mortality in women. Despite extensive efforts to identify valid biomarkers for risk stratification, there are relatively few with proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to breast cancer. Recent genome-wide-association-studies and gene expression analysis have demonstrated that a locus on chromosome 9p21, which contains three genes; CDKN2B (encoding p15ink4b), CDKN2A (encoding p16ink4a and p14ARF) and the 3' end of CDKN2BAS [an antisense noncoding RNA in the INK4 locus (ANRIL)] are associated with an increased risk of this malignancy...
December 14, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29228217/p19arf-inhibits-aggressive-progression-of-h-ras-driven-hepatocellular-carcinoma
#4
Dragana Kopanja, Akshay Pandey, Shuo Huang, Mohamed Rizwan Haroon Al Raheed, Grace Guzman, Pradip Raychaudhuri
Arf, a well-established tumor suppressor, is either mutated or downregulated in a wide array of cancers. However, its role in hepatocellular carcinoma (HCC) progression is controversial. Conflicting observations have been published regarding its expression in HCC. In this study, we provide clear genetic evidence demonstrating a protective role of p19Arf in hepatocarcinogenesis. Using Ras-induced mouse model, we show that p19Arf deficiency accelerates progression of aggressive HCC in vivo. To investigate the role of p14ARF in human liver cancers, we analyzed its expression in human HCC using immunohistochemistry...
December 8, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29115399/loss-of-the-clock-gene-per2-is-associated-with-cancer-development-and-altered-expression-of-important-tumor-related-genes-in-oral-cancer
#5
Honggang Xiong, Yixin Yang, Kai Yang, Dan Zhao, Hong Tang, Xiongwen Ran
Recent studies have demonstrated that abnormal expression of the clock gene PER2 is closely associated with the development of a variety of cancer types. However, the expression of PER2 in oral squamous cell carcinoma (OSCC), a common malignant tumor in humans, and its correlations with the clinicopathological parameters and survival time of OSCC patients and the altered expression of important tumor-related genes remain unclear. In the present study, we detected the mRNA and protein expression levels of PER2, PIK3CA, PTEN, P53, P14ARF and caspase‑8 in OSCC tissues and cancer-adjacent oral mucosa by reverse transcription-quantitative PCR (RT-qPCR), western blotting and immunohistochemistry...
October 31, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28754531/carf-is-a-multi-module-regulator-of-cell-proliferation-and-a-molecular-bridge-between-cellular-senescence-and-carcinogenesis
#6
REVIEW
Renu Wadhwa, Rajkumar Singh Kalra, Sunil C Kaul
CARF (Collaborator of ARF) was first identified as an ARF (Alternative Reading Frame, p14ARF)-interacting protein in a yeast two-hybrid interactive screening. Subsequently, it was shown to stabilize the p53-tumor suppressor protein in an ARF-dependent or -independent manner. It acts as a transcriptional repressor of HDM2 that exerts a negative feedback on p53 by its proteasomal-mediated degradation. CARF-driven control over p53-HDM2-p21(WAF1) axis was shown to regulate cell proliferative fates. Cells with CARF-overexpression (CARF-OE) and superexpression (CARF-SE) showed growth arrest and pro-proliferative phenotypes, respectively...
July 25, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28711940/clinical-significance-of-p16ink4a-and-p14arf-promoter-methylation-in-renal-cell-carcinoma-a-meta-analysis
#7
Yu Ren, Li Xiao, Guobin Weng, Bingyi Shi
The inactivation of p16INK4A and p14ARF via promoter methylation has been investigated in various cancers. However, the clinical effects of p16INK4A and p14ARF promoter methylation on renal cell carcinoma (RCC) remain to be clarified. The pooled data were calculated and summarized. Finally, an investigation of 14 eligible studies with 1231 RCC patients and 689 control patients was performed. Methylated p16INK4A and p14ARF were observed to be significantly higher in RCC than in control subjects without malignancies (OR = 2...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28529622/ires-mediated-protein-translation-overcomes-suppression-by-the-p14arf-tumor-suppressor-protein
#8
Song Xi, Ming Zhao, Si Wang, Ling Ma, Shensen Wang, Xianling Cong, Ruth A Gjerset, Rebecca C Fitzgerald, Yinghui Huang
Internal ribosome entry sites (IRES elements) have attracted interest in cancer gene therapy because they can be used in the design of gene transfer vectors that provide bicistronic co-expression of two transgene products under the control of a single promoter. Unlike cellular translation of most mRNAs, a process that requires a post-translational 5' modification of the mRNA known as the cap structure, IRES-mediated translation is independent of the cap structure. The cellular conditions that may intervene to modulate IRES-mediated, cap-independent versus cap-dependent translation, however, remain poorly understood, although they could be critical to the choice of gene transfer vectors...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28436949/p14arf-interacts-with-the-focal-adhesion-kinase-and-protects-cells-from-anoikis
#9
M Vivo, R Fontana, M Ranieri, G Capasso, T Angrisano, A Pollice, V Calabrò, G La Mantia
The ARF protein functions as an important sensor of hyper-proliferative stimuli restricting cell proliferation through both p53-dependent and -independent pathways. Although to date the majority of studies on ARF have focused on its anti-proliferative role, few studies have addressed whether ARF may also have pro-survival functions. Here we show for the first time that during the process of adhesion and spreading ARF re-localizes to sites of active actin polymerization and to focal adhesion points where it interacts with the phosphorylated focal adhesion kinase...
August 24, 2017: Oncogene
https://www.readbyqxmd.com/read/28431405/usp5-functions-as-an-oncogene-for-stimulating-tumorigenesis-in-hepatocellular-carcinoma
#10
Yi Liu, Wei-Mao Wang, Ying-Fei Lu, Lu Feng, Li Li, Ming-Zhu Pan, Yu Sun, Chun-Wai Suen, Wei Guo, Jian-Xin Pang, Jin-Fang Zhang, Wei-Ming Fu
As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis...
April 6, 2017: Oncotarget
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
#11
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 21, 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
#12
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
#13
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...
April 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
#14
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...
July 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
#15
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
#16
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-p16-ink4a-and-p14-arf-pathways-overcomes-apoptosis-in-individualized-human-embryonic-stem-cells
#17
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 naive 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...
March 2017: 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
#18
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
#19
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
#20
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
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