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https://www.readbyqxmd.com/read/28099441/puma-and-nf-kb-are-cell-signaling-predictors-of-reovirus-oncolysis-of-breast-cancer
#1
Chandini Thirukkumaran, Zhong-Qiao Shi, Ponnampalam Thirukkumaran, Joanne Luider, Karen Kopciuk, Jason Spurrell, Kate Elzinga, Don Morris
BACKGROUND AND PURPOSE: Reovirus is a ubiquitous RNA virus that exploits aberrant signaling pathways for its replication. The oncolytic potential of reovirus against numerous cancers under pre-clinical/clinical conditions has been documented by us and others. Despite its proven clinical activity, the underlying mechanisms of reovirus oncolysis is still not well elucidated. If reovirus therapy is to be optimized for cancer, including breast cancer patients, it is imperative to understand the mechanisms of reovirus oncolysis, especially in treatment of resistant tumour...
2017: PloS One
https://www.readbyqxmd.com/read/28097652/mdm4-is-a-rational-target-for-treating-breast-cancers-with-mutant-p53
#2
Panimaya Jeffreena Miranda, Daniel Buckley, Dinesh Raghu, Jia-Min B Pang, Elena A Takano, Reshma Vijayakumaran, Amina F A S Teunisse, Atara Posner, Tahlia Procter, Marco J Herold, Cristina Gamell, Jean-Christophe Marine, Stephen B Fox, Aart Jochemsen, Sue Haupt, Ygal Haupt
Mutation of the key tumour suppressor p53 defines a transition in the progression toward aggressive and metastatic breast cancer (BC) with the poorest outcome. Specifically, p53 mutation frequency exceeds 50% in Triple Negative BC (TNBC). Key regulators of mutant p53 that facilitate its oncogenic functions are potential therapeutic targets. We report here that the MDM4 protein is frequently abundant in the context of mutant p53 in basal-like BC samples. Importantly, we show that MDM4 plays a critical role in the proliferation of these BC cells...
January 18, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28077648/human-papillomavirus-16-e6-up-regulates-apobec3b-via-the-tead-transcription-factor
#3
Seiichiro Mori, Takamasa Takeuchi, Yoshiyuki Ishii, Takashi Yugawa, Tohru Kiyono, Hiroshi Nishina, Iwao Kukimoto
: The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28071670/benzyl-isothiocyanate-potentiates-p53-signaling-and-antitumor-effects-against-breast-cancer-through-activation-of-p53-lkb1-and-p73-lkb1-axes
#4
Bei Xie, Arumugam Nagalingam, Panjamurthy Kuppusamy, Nethaji Muniraj, Peter Langford, Balázs Győrffy, Neeraj K Saxena, Dipali Sharma
Functional reactivation of p53 pathway, although arduous, can potentially provide a broad-based strategy for cancer therapy owing to frequent p53 inactivation in human cancer. Using a phosphoprotein-screening array, we found that Benzyl Isothiocynate, (BITC) increases p53 phosphorylation in breast cancer cells and reveal an important role of ERK and PRAS40/MDM2 in BITC-mediated p53 activation. We show that BITC rescues and activates p53-signaling network and inhibits growth of p53-mutant cells. Mechanistically, BITC induces p73 expression in p53-mutant cells, disrupts the interaction of p73 and mutant-p53, thereby releasing p73 from sequestration and allowing it to be transcriptionally active...
January 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#5
Xiaoqi Liu, Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069388/vitamin-d-receptor-deficit-induces-activation-of-renin-angiotensin-system-via-sirt1-modulation-in-podocytes
#6
Nirupama Chandel, Kamesh Ayasolla, Hongxiu Wen, Xiqian Lan, Shabirul Haque, Moin A Saleem, Ashwani Malhotra, Pravin C Singhal
Vitamin D receptor (VDR) deficient status has been shown to be associated with the activation of renin angiotensin system (RAS). We hypothesized that lack of VDR would enhance p53 expression in podocytes through down regulation of SIRT1; the former would enhance the transcription of angiotensinogen (Agt) and angiotensinogen II type 1 receptor (AT1R) leading to the activation of RAS. Renal tissues of VDR mutant (M) mice displayed increased expression of p53, Agt, renin, and AT1R. In vitro studies, VDR knockout podocytes not only displayed up regulation p53 but also displayed enhanced expression of Agt, renin and AT1R...
January 6, 2017: Experimental and Molecular Pathology
https://www.readbyqxmd.com/read/28068330/loss-of-p53-induces-leukemic-transformation-in-a-murine-model-of-jak2-v617f-driven-polycythemia-vera
#7
T Tsuruta-Kishino, J Koya, K Kataoka, K Narukawa, Y Sumitomo, H Kobayashi, T Sato, M Kurokawa
As leukemic transformation of myeloproliferative neoplasms (MPNs) worsens the clinical outcome, reducing the inherent risk of the critical event in MPN cases could be beneficial. Among genetic alterations concerning the transformation, the frequent one is TP53 mutation. Here we show that retroviral overexpression of Jak2 V617F mutant into wild-type p53 murine bone marrow cells induced polycythemia vera (PV) in the recipient mice, whereas Jak2 V617F-transduced p53-null mice developed lethal leukemia after the preceding PV phase...
January 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28060750/hipk2-t566-autophosphorylation-diversely-contributes-to-uv-and-doxorubicin-induced-hipk2-activation
#8
Alessandra Verdina, Giuliana Di Rocco, Ilaria Virdia, Laura Monteonofrio, Veronica Gatti, Eleonora Policicchio, Alessandro Bruselles, Marco Tartaglia, Silvia Soddu
HIPK2 is a Y-regulated S/T kinase involved in various cellular processes, including cell-fate decision during development and DNA damage response. Cis-autophosphorylation in the activation-loop and trans-autophosphorylation at several S/T sites along the protein are required for HIPK2 activation, subcellular localization, and subsequent posttranslational modifications. The specific function of a few of these autophosphorylations has been recently clarified; however, most of the sites found phosphorylated by mass spectrometry in human and/or mouse HIPK2 are still uncharacterized...
January 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28057708/development-of-an-in-vitro-pig-a-gene-mutation-assay-in-human-cells
#9
Benjamin J Rees, Matthew Tate, Anthony M Lynch, Catherine A Thornton, Gareth J Jenkins, Richard M Walmsley, George E Johnson
Mutagens can be carcinogens, and traditionally, they have been identified in vitro using the Salmonella 'Ames' reverse mutation assay. However, prokaryotic DNA packaging, replication and repair systems are mechanistically very different to those in the humans we inevitably seek to protect. Therefore, for many years, mammalian cell line genotoxicity assays that can detect eukaryotic mutagens as well as clastogens and aneugens have been used. The apparent lack of specificity in these largely rodent systems, due partly to their mutant p53 status, has contributed to the use of animal studies to resolve data conflicts...
January 4, 2017: Mutagenesis
https://www.readbyqxmd.com/read/28055106/imidazoquinoxaline-derivative-eapb0503-a-promising-drug-targeting-mutant-nucleophosmin-1-in-acute-myeloid-leukemia
#10
Ali I Nabbouh, Rita S Hleihel, Jessica L Saliba, Martin M Karam, Maguy H Hamie, Hsin-Chieh J M Wu, Caroline P Berthier, Nadim M Tawil, Pierre-Antoine A Bonnet, Carine Deleuze-Masquefa, Hiba A El Hajj
BACKGROUND: Nucleophosmin 1 (NPM1) is a nucleocytoplasmic shuttling protein mainly localized in the nucleolus. NPM1 is frequently mutated in acute myeloid leukemia (AML). NPM1c oligomerizes with wild-type nucleophosmin 1 (wt-NPM1), and this leads to its continuous cytoplasmic delocalization and contributes to leukemogenesis. Recent studies have shown that Cytoplasmic NPM1 (NPM1c) degradation leads to growth arrest and apoptosis of NPM1c AML cells and corrects wt-NPM1 normal nucleolar localization...
January 5, 2017: Cancer
https://www.readbyqxmd.com/read/28053547/anticancer-activities-of-epigallocatechin-3-gallate-against-cholangiocarcinoma-cells
#11
Tae Won Kwak, Su Bum Park, Hyun-Jung Kim, Young-Il Jeong, Dae Hwan Kang
PURPOSE: Epigallocatechin-3-gallate (EGCG) is an antioxidant agent derived from green tea. Because it has chemopreventive and anti-invasive effect against various cancer cells, EGCG can be used to inhibit proliferation and invasion of cholangiocarcinoma (CCA) cells. METHODS: The anticancer effects of EGCG were studied using human CCA cells (HuCC-T1). Apoptosis was analyzed by Western blotting. Invasion and migration of cancer cells were assessed with Matrigel(®) and wound healing assays...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28052119/pre-clinical-study-of-panobinostat-in-xenograft-and-genetically-engineered-murine-diffuse-intrinsic-pontine-glioma-models
#12
Tammy Hennika, Guo Hu, Nagore G Olaciregui, Kelly L Barton, Anahid Ehteda, Arjanna Chitranjan, Cecilia Chang, Andrew J Gifford, Maria Tsoli, David S Ziegler, Angel M Carcaboso, Oren J Becher
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. METHODS: A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3...
2017: PloS One
https://www.readbyqxmd.com/read/28038466/drug-dependent-functionalization-of-wild-type-and-mutant-p53-in-cisplatin-resistant-human-ovarian-tumor-cells
#13
Michelle Bhatt, Cristina Ivan, Xiaolei Xie, Zahid H Siddik
Cisplatin (cis-Pt) resistance in tumor cells from p53 dysfunction is a significant clinical problem. Although mutation can inhibit p53 function, >60% of p53 mutants retain normal function according to literature reports. Therefore, we examined the status of p53 in cisplatin-resistant ovarian tumor models and its functional response to cis-Pt and the mechanistically-distinct non-cross-resistant oxaliplatin (oxali-Pt). Relative to sensitive A2780 cells harboring wild-type p53, the 2780CP/Cl-16, OVCAR-10, Hey and OVCA-433 cell lines were 10- to 30-fold resistant to cis-Pt, but was substantially circumvented by oxali-Pt...
December 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/28035683/nuclear-inclusion-bodies-of-mutant-and-wild-type-p53-in-cancer-a-hallmark-of-p53-inactivation-and-proteostasis-remodeling-by-p53-aggregation
#14
Frederik De Smet, Mirian Saiz Rubio, Daphne Hompes, Evelyne Naus, Greet De Baets, Tobias Langenberg, Mark S Hipp, Bert Houben, Filip Claes, Sarah Charbonneau, Javier Delgado Blanco, Stephane Plaisance, Shakti Ramkissoon, Lori Ramkissoon, Colinda Simons, Piet van den Brandt, Matty Weijenberg, Manon Van England, Sandrina Lambrechts, Frederic Amant, André D'Hoore, Keith L Ligon, Xavier Sagaert, Joost Schymkowitz, Frederic Rousseau
Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders...
December 30, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/28035352/expression-of-ribophorine-ii-is-a-promising-prognostic-factor-in-human-gastric-adenocarcinoma
#15
Daisuke Fujimoto, Takanori Goi, Yasuo Hirono
The increased invasiveness of gastric adenocarcinoma is important for progression and metastasis. In recent molecular biological studies, ribophorine II (RPN2) induced epithelial-mesenchymal transition and metastatic activity. However, no studies have evaluated the relationship between RPN2 expression, ability of cancer to invade/metastasis, and patient prognosis in gastric adenocarcinoma. Therefore, we have examined these factors. Immunohistochemical staining was performed to detect RPN2 and p53 in the primary lesion and adjacent normal gastric mucosa of 242 gastric adenocarcinoma patients who underwent resection surgery...
February 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28032868/differential-regulated-microrna-by-wild-type-and-mutant-p53-in-induced-pluripotent-stem-cells
#16
Francesca Grespi, Vivien Landré, Alina Molchadsky, Nicola Di Daniele, Luigi Tonino Marsella, Gerry Melino, Varda Rotter
The tumour suppressor p53 plays an important role in somatic cell reprogramming. While wild-type p53 reduces reprogramming efficiency, mutant p53 exerts a gain of function activity that leads to increased reprogramming efficiency. Furthermore, induced pluripotent stem cells expressing mutant p53 lose their pluripotency in vivo and form malignant tumours when injected in mice. It is therefore of great interest to identify targets of p53 (wild type and mutant) that are responsible for this phenotype during reprogramming, as these could be exploited for therapeutic use, that is, formation of induced pluripotent stem cells with high reprogramming efficiency, but no oncogenic potential...
December 29, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/28032649/kras-mutation-coupled-with-p53-loss-is-sufficient-to-induce-ovarian-carcinosarcomas-in-mice
#17
Feng-Hsiang Tang, Tsung-Hua Hsieh, Chia-Yi Hsu, Hsiao-Yun Lin, Cheng-Yu Long, Kuang-Hung Cheng, Eing-Mei Tsai
Ovarian carcinosarcoma cancer is the most lethal form of gynecological malignancy, but the pathogenesis and biological function for this ovarian cancer remain unknown. We establishment the transgenic mouse model of K-ras(G12D) p53(loxP/loxP) and found that K-ras mutation and p53 deletion within the ovarian surface epithelium gave rise to ovarian lesions with a hyperproliferation and endometrioid glandular morphology. Furthermore, double mutant ovaries formed ovarian carcinosarcomas that were high grade and poorly differentiated...
December 29, 2016: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28031409/functional-activation-of-mutant-p53-by-platinum-analogs-in-cisplatin-resistant-cells-is-dependent-on-phosphorylation
#18
Xiaolei Xie, Guangan He, Zahid H Siddik
: Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently we reported that mutant, but otherwise functional, p53V172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogs oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP), strongly stabilize and activate p53V172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2...
December 28, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28025407/altered-s-nitrosylation-of-p53-is-responsible-for-impaired-antioxidant-response-in-skeletal-muscle-during-aging
#19
Sara Baldelli, Maria Rosa Ciriolo
p53 transcriptional activity has been proposed to regulate both homeostasis and sarcopenia of skeletal muscle during aging. However, the exact molecular function of p53 remains to be clearly defined. We demonstrated a requirement of nuclear p53 S-nitrosylation in inducing a nitric oxide/PGC-1α-mediated antioxidant pathway in skeletal muscle. Importantly, mutant form of p53-DNA binding domain (C124S) did not undergo nuclear S-nitrosylation and failed in inducing the expression of antioxidant genes (i.e. SOD2 and GCLC)...
December 20, 2016: Aging
https://www.readbyqxmd.com/read/28008605/immune-deficiency-augments-the-prevalence-of-p53-loss-of-heterozygosity-in-spontaneous-tumors-but-not-bi-directional-loss-of-heterozygosity-in-bone-marrow-progenitors
#20
Yoav Shetzer, Yael Napchan, Tom Kaufman, Alina Molchadsky, Perry Tal, Naomi Goldfinger, Varda Rotter
p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo. Surprisingly, the loss of either the wild-type p53 allele or mutant p53 allele was detected with a three-to-one ratio in favor of losing the mutant allele. In the present study we examined whether the immune-system can affect the LOH directionality in bone marrow progenitors...
December 22, 2016: International Journal of Cancer. Journal International du Cancer
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