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https://www.readbyqxmd.com/read/28916678/gucy2c-signaling-opposes-the-acute-radiation-induced-gi-syndrome
#1
Peng Li, Evan Wuthrick, Jeff A Rappaport, Crystal Kraft, Jieru E Lin, Glen Marszalowicz, Adam E Snook, Tingting Zhan, Terry M Hyslop, Scott A Waldman
High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28916339/d-amino-acid-mutation-of-pmi-as-potent-dual-peptide-inhibitors-of-p53-mdm2-mdmx-interactions
#2
Xiang Li, Chao Liu, Si Chen, Honggang Hu, Jiacan Su, Yan Zou
According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs.
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28915653/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#3
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28910957/-effects-of-cell-cycle-regulatory-genes-on-breast-cancer-neo-adjuvant-chemotherapy-by-m-fish
#4
C Y Li, W Su, S Zhang, Y H Hu, J J Liu, J Zhang
Objective: The dysregulation of cell cycle could influence cell proliferation, differentiation and response to medicine. The purpose of this study is to explore the correlation between cell cycle regulatory genes and breast cancer neo-adjuvant chemotherapy (NAC) in patients with local advanced breast cancer, and thus to find some predictors of NAC to provide guidance for clinical treatment. Methods: Ninety five cases of local advanced breast cancer were collected, which were treated with NAC of TAC (Taxanes/Anthracycline/Cyclophosphamide) regimen...
September 12, 2017: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/28910819/mechanisms-of-targeting-the-mdm2-p53-foxm1-axis-in-well-differentiated-intestinal-neuroendocrine-tumors
#5
Irina Grass, Franziska Briest, Dagmar Sedding, Markus Möbs, Friederike Christen, Joana Benecke, Karolin Fuchs, Daniel Kaemmerer, Stefanie Mende, Jörg Sänger, Almut Kunze, Christina Geisler, Helma Freitag, Florentine Lewens, Lina Worpenberg, Sara Iwaszkiewicz, Britta Siegmund, Wolfgang Walther, Michael Hummel, Patricia Grabowski
<br>Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of p53 negative regulators, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. METHODS: By western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN...
September 14, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28904012/identification-of-a-core-tp53-transcriptional-program-with-highly-distributed-tumor-suppressive-activity
#6
Zdenek Andrysik, Matthew D Galbraith, Anna L Guarnieri, Sara Zaccara, Kelly D Sullivan, Ahwan Pandey, Morgan MacBeth, Alberto Inga, Joaquín M Espinosa
The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53...
September 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28903316/mdm2-antagonists-synergize-with-pi3k-mtor-inhibition-in-well-differentiated-dedifferentiated-liposarcomas
#7
Audrey Laroche, Vanessa Chaire, Marie-Paule Algeo, Marie Karanian, Benjamin Fourneaux, Antoine Italiano
BACKGROUND: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) are characterized by a consistent amplification of the MDM2 gene. The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis. Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS. METHODS: WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 (PI3K/mTOR dual inhibitor) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28892044/a-novel-mouse-model-of-rhabdomyosarcoma-underscores-the-dichotomy-of-mdm2-alt1-function-in-vivo
#8
D F Comiskey, A G Jacob, B L Sanford, M Montes, A K Goodwin, H Steiner, E Matsa, A S Tapia-Santos, T W Bebee, J Grieves, K La Perle, P Boyaka, D S Chandler
Alternative splicing of the oncogene murine double minute 2 (MDM2) is induced in response to genotoxic stress. MDM2-ALT1, the major splice variant generated, is known to activate the p53 pathway and impede full-length MDM2's negative regulation of p53. Despite this perceptible tumor-suppressive role, MDM2-ALT1 is also associated with several cancers. Furthermore, expression of MDM2-ALT1 has been observed in aggressive metastatic disease in pediatric rhabdomyosarcoma (RMS), irrespective of histological subtype...
September 11, 2017: Oncogene
https://www.readbyqxmd.com/read/28887581/multiple-skeletal-muscle-metastases-revealing-a-cardiac-intimal-sarcoma
#9
Amandine Crombé, Pierre-François Lintingre, François Le Loarer, Denis Lachatre, Benjamin Dallaudière
We report the case of a 59-year-old female with progressive bilateral painful swelling of the thighs. MRI revealed multiple intramuscular necrotic masses with similar morphologic patterns. Whole-body CT and 18-FDG PET-CT scans demonstrated additional hypermetabolic muscular masses and a lobulated lesion within the left atrial cavity. As biopsy of a muscular mass was compatible with a poorly differentiated sarcoma with MDM2 oncogene amplification, two diagnoses were discussed: a dedifferentiated liposarcoma with muscle and heart metastases or a primary cardiac sarcoma, mainly a cardiac intimal sarcoma, with muscular metastases, which was finally confirmed by array-comparative genomic hybridization (aCGH) in a sarcoma reference center...
September 8, 2017: Skeletal Radiology
https://www.readbyqxmd.com/read/28885617/post-translational-regulation-of-p53-function-through-20s-proteasome-mediated-cleavage
#10
Hilla Solomon, Bastian Bräuning, Irit Fainer, Gili Ben-Nissan, Stav Rabani, Naomi Goldfinger, Oren Moscovitz, Zippora Shakked, Varda Rotter, Michal Sharon
The tumor suppressor p53 is a transcription factor that regulates the expression of a range of target genes in response to cellular stress. Adding to the complexity of understanding its cellular function is that in addition to the full-length protein, several p53 isoforms are produced in humans, harboring diverse expression patterns and functionalities. One isoform, Δ40p53, which lacks the first transactivation domain including the binding region for the negative regulator MDM2, was shown to be a product of alternative translation initiation...
September 8, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28885338/association-between-mdm2-snp309-p53-arg72pro-and-hepatocellular-carcinoma-risk-a-moose-compliant-meta-analysis
#11
Xiaohua Duan, Jingquan Li
Epidemiological studies have determined the associations between polymorphisms on the promoter of MDM2 (SNP309) and the codon 72 on exon 4 of p53 (p53 Arg72Pro) and the risk of hepatocellular carcinoma (HCC); however, the results were not always consistent. The aim of the present meta-analysis was to evaluate the overall associations between these 2 variants and HCC risk.The MEDLINE, Web of science, EMBASE, Cochrane Library, and CNKI databases were searched for eligibility studies and the data were synthesized under the fixed- or random-effects model...
September 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28881764/detection-of-nasopharyngeal-carcinoma-susceptibility-with-single-nucleotide-polymorphism-analysis-using-next-generation-sequencing-technology
#12
Mu-Yun Wu, Shu-Jing Huang, Fan Yang, Xin-Tian Qin, Dong Liu, Ying Ding, Shu Yang, Xi-Cheng Wang
Nasopharyngeal carcinoma (NPC) is a head and neck cancer with high incidence in South China and East Asia. To provide a theoretical basis for NPC risk screening and early prevention, we conducted a meta-analysis of relevant literature on the association of single nucleotide polymorphisms (SNP)s with NPC susceptibility. Further, expression of 15 candidate SNPs identified in the meta-analysis was evaluated in a cohort of NPC patients and healthy volunteers using next-generation sequencing technology. Among the 15 SNPs detected in the meta-analysis, miR-146a (rs2910164, C>G), HCG9 (rs3869062, A>G), HCG9 (rs16896923, T>C), MMP2 (rs243865, C>T), GABBR1 (rs2076483, T>C), and TP53 (rs1042522, C>G) were associated with decreased susceptibility to NPC, while GSTM1 (+/DEL), IL-10 (rs1800896, A>G), MDM2 (rs2279744, T>G), MDS1-EVI1 (rs6774494, G>A), XPC (rs2228000, C>T), HLA-F (rs3129055, T>C), SPLUNC1 (rs2752903, T>C; and rs750064, A>G), and GABBR1 (rs29232, G>A) were associated with increased susceptibility to NPC...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878120/mdm2-regulates-cardiac-contractility-by-inhibiting-grk2-mediated-desensitization-of-%C3%AE-adrenergic-receptor-signaling
#13
Pierre-Yves Jean-Charles, Samuel Mon-Wei Yu, Dennis Abraham, Reddy Peera Kommaddi, Lan Mao, Ryan T Strachan, Zhu-Shan Zhang, Dawn E Bowles, Leigh Brian, Jonathan A Stiber, Stephen N Jones, Walter J Koch, Howard A Rockman, Sudha K Shenoy
The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, thereby regulating β-adrenergic receptor (βAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects βAR signaling and cardiac function in adult mice...
September 7, 2017: JCI Insight
https://www.readbyqxmd.com/read/28871352/co-operative-intra-protein-structural-response-due-to-protein-protein-complexation-revealed-through-thermodynamic-quantification-study-of-mdm2-p53-binding
#14
Sudipta Samanta, Sanchita Mukherjee
The p53 protein activation protects the organism from propagation of cells with damaged DNA having oncogenic mutations. In normal cells, activity of p53 is controlled by interaction with MDM2. The well understood p53-MDM2 interaction facilitates design of ligands that could potentially disrupt or prevent the complexation owing to its emergence as an important objective for cancer therapy. However, thermodynamic quantification of the p53-peptide induced structural changes of the MDM2-protein remains an area to be explored...
September 4, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28871126/mdm2-contributes-to-high-glucose-induced-glomerular-mesangial-cell-proliferation-and-extracellular-matrix-accumulation-via-notch1
#15
Chun-Tao Lei, Hui Tang, Chen Ye, Chao-Qun You, Jiao Zhang, Chun-Yun Zhang, Wei Xiong, Hua Su, Chun Zhang
Murine double minute 2 (MDM2) is an E3-ubiquitin ligase critical for various biological functions. Previous data have revealed an indispensable role of MDM2 in kidney homeostasis. However, its role in glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation during hyperglycemia condition remains unclear. In our present study, we found that MDM2 protein level was significantly upregulated in high glucose-treated GMCs, while knocking down MDM2 by siRNA could attenuate high glucose-induced ECM accumulation and GMCs proliferation...
September 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28867193/trim25-is-associated-with-cisplatin-resistance-in-non-small-cell-lung-carcinoma-a549%C3%A2-cell-line-via-downregulation-of-14-3-3%C3%AE
#16
Xia Qin, Feng Qiu, Zhen Zou
Lung cancer, in particular, non-small cell lung cancer (NSCLC), is the leading cause of cancer-related mortality. Cis-Diamminedichloroplatinum (cisplatin, CDDP) as first-line chemotherapy for NSCLC, but resistance occurs frequently. We previously reported that Tripartite motif protein 25 (TRIM25) was highly expressed in cisplatin-resistant human lung adenocarcinoma A549 cells (A549/CDDP) in comparison with its parental A549 cells. Herein, we take a further step to demonstrate the association of TRIM25 and cisplatin resistance and also the underlying mechanisms...
August 31, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28866417/effects-of-ganoderma-lucidum-polysaccharides-against-doxorubicin-induced-cardiotoxicity
#17
Fan Xu, Xiao Li, Xu Xiao, Lan-Fang Liu, Li Zhang, Ping-Ping Lin, Sheng-Lin Zhang, Qing-Shan Li
Doxorubicin (DOX) is a widely used anthracycline derivative anticancer drug, but the use of DOX in clinical applications is limited by its cardiotoxicity. In the current research, we were aiming to assess the effects of Ganoderma lucidum polysaccharides (GLPS) on DOX-induced cardiotoxicity and to illustrate the associated mechanisms. H9c2 rat cardiomyocytes were treated with DOX in the absence or presence of GLPS, and we found GLPS treatment ameliorated DOX-induced H9c2 cell death. Moreover, results of in vivo studies indicated that GLPS significantly decreased the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and aspartate aminotransferase (AST) and attenuated DOX-induced histological changes of the heart tissues...
August 31, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28864908/antitumor-activity-and-expression-profiles-of-genes-induced-by-sulforaphane-in-human-melanoma-cells
#18
Paola Arcidiacono, Francesco Ragonese, Anna Stabile, Alessandra Pistilli, Ekaterina Kuligina, Mario Rende, Ugo Bottoni, Stefano Calvieri, Andrea Crisanti, Roberta Spaccapelo
PURPOSE: Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown. METHODS: Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa)...
September 1, 2017: European Journal of Nutrition
https://www.readbyqxmd.com/read/28864115/rasgrp3-controls-cell-proliferation-and-migration-in-papillary-thyroid-cancer-by-regulating-the-akt-mdm2-pathway
#19
Wangwang Qiu, Xiaotian Xia, Zhongling Qiu, Minggao Guo, Zhili Yang
Accumulating evidence has shown that Ras guanylnucleotide releasing peptide 3 (RasGRP3) is up-regulated in several distinct cancer types; however, its role in papillary thyroid cancer (PTC) remains unclear. In this study, we demonstrate that RasGRP3 was overexpressed in PTC tissues and cell lines. Downregulation of RasGRP3 using small interfering (si) RNA significantly inhibited PTC cell proliferation and migration in vitro, and tumor growth in vivo, reflecting an oncogenic role of RasGRP3 in PTC. We subsequently identified that the expression of mouse double minute 2 homolog (MDM2) and phosphorylated Akt (p-Akt) was significantly decreased in RasGRP3-downregulated PTC cells...
August 29, 2017: Gene
https://www.readbyqxmd.com/read/28859621/nat10-is-upregulated-in-hepatocellular-carcinoma-and-enhances-mutant-p53-activity
#20
Qijiong Li, Xiaofeng Liu, Kemin Jin, Min Lu, Chunfeng Zhang, Xiaojuan Du, Baocai Xing
BACKGROUND: N-acetyltransferase 10 (NAT10) is a histone acetyltransferase which is involved in a wide range of cellular processes. Recent evidences indicate that NAT10 is involved in the development of human cancers. Previous study showed that NAT10 acetylates the tumor suppressor p53 and regulates p53 activation. As Tp53 gene is frequently mutated in hepatocellular carcinoma (HCC) and associates with the occurrence and development of HCC, the relationship between NAT10 and HCC was investigated in this study...
August 31, 2017: BMC Cancer
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