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p53 mdm2

Qian Wang, Narayan Acharya, Zhongwei Liu, Xianmei Zhou, Meghan Cromie, Jia Zhu, Weimin Gao
ETHNOPHARMACOLOGICAL RELEVANCE: Experience-based herbal medicine as a complementary to modern western medicine has triggered an array of studies in quest of novel anticancer drugs. Scutellaria barbata D. Don (SB) is commonly used to treat different types of cancers, but its molecular mechanism of action is not clearly understood. In this study, we attempted to elucidate the mode of action of a traditional Chinese medicine prescription with a total of 14 components, named Lian-Jia-San-Jie-Fang (LJSJF, in Chinese), where SB works as the "principle" against non-small cell lung cancer (NSCLC) cells...
February 16, 2018: Journal of Ethnopharmacology
Giuseppe Arena, Madi Yann Cissé, Samuel Pyrdziak, Laurent Chatre, Romain Riscal, Maryse Fuentes, Jamie Jon Arnold, Markus Kastner, Laurie Gayte, Christelle Bertrand-Gaday, Kevin Nay, Claire Angebault-Prouteau, Kerren Murray, Beatrice Chabi, Christelle Koechlin-Ramonatxo, Béatrice Orsetti, Charles Vincent, François Casas, Jean-Christophe Marine, Sandrine Etienne-Manneville, Florence Bernex, Anne Lombès, Craig Eugene Cameron, Hervé Dubouchaud, Miria Ricchetti, Laetitia Karine Linares, Laurent Le Cam
Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production...
February 15, 2018: Molecular Cell
Michaela Angelika Ihle, Sebastian Huss, Wiebke Jeske, Wolfgang Hartmann, Sabine Merkelbach-Bruse, Hans-Ulrich Schildhaus, Reinhard Büttner, Harri Sihto, Kirsten Sundby Hall, Mikael Eriksson, Peter Reichardt, Heikki Joensuu, Eva Wardelmann
Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy...
2018: PloS One
Yu-Chin Su, Latif Reshi, Lei-Jia Chen, Wei-Han Li, Hsuan-Wen Chiu, Jiann-Ruey Hong
The molecular functions of betanodavirus non-structural protein B and its role in host cell survival remain unclear. In the present study, we examined the roles of specific nuclear targeting domains in B1 localization as well as the effect of B1 nuclear localization on the cell cycle and host cell survival. The B1 protein of the Red spotted grouper nervous necrosis virus (RGNNV) was detected in GF-1 grouper cells as early as 24 hours post-infection (hpi). Using an EYFP-B1 fusion construct, we observed nuclear localization of the B1 protein (up to 99%) in GF-1 cells at 48 hpi...
February 15, 2018: Scientific Reports
Xingwang Xie, Xueyan Wang, Weijia Liao, Ran Fei, Nan Wu, Xu Cong, Qian Chen, Lai Wei, Yu Wang, Hongsong Chen
BACKGROUND: Identification of novel MDM2 or p53 binding proteins may reveal undefined oncogenes, tumor suppressors, signaling pathways and possible treatment targets. METHODS: By means of immunoprecipitation and Mass Spectrometry analysis, we aimed to identify novel regulators of the MDM2-p53 pathway. We further clarified the impact of MYL6B on the p53 protein level and on the process of apoptosis. We also investigated the role of MYL6B in hepatocellular carcinoma by clone formation assay and by determining the correlation between its expression and prognosis of HCC patients...
February 13, 2018: Journal of Experimental & Clinical Cancer Research: CR
Yang Han, Chenlong Song, Jianying Wang, Huamei Tang, Zhihai Peng, Su Lu
5-FU-based chemotherapy is recently most recommended as the first-line treatment for gastric cancer (GC). However, 5-FU resistance is common for many postoperative GC patients. Homeobox A13 (HOXA13) is a member of homeobox genes highly expressed in many human tumors. Its potential roles and mechanisms of resistance to 5-FU in GC are poorly understood. In this study, we discovered that HOXA13 played an oncogenic role in vivo and in vitro. The patients with HOXA13 overexpression were closely related with poor prognosis and more prone to be resistant to 5-FU...
February 13, 2018: Molecular Carcinogenesis
Yao Shi, Chen Lv, Li Shi, Guanjun Tu
Osteosarcoma is known as a malignant tumour with a high mortality rate in orthopaedic settings; however, the factors associated with its degree of malignancy and the biological response remains to be elucidated. Although the essential role of the long noncoding RNA (lncRNA) maternally expressed 3 (MEG3) has been recently reported, its biological functions and regulatory mechanism in osteosarcoma cells have not yet been reported. In the present study, reverse transcription-quantitative polymerase chain reaction analysis revealed that the expression of MEG3 in MG63 cells was lower compared with in hFOB1...
February 2018: Oncology Letters
Michal Štros, Martin Kučírek, Soodabeh Abbasi Sani, Eva Polanská
HMGB1 is a chromatin-associated protein that has been implicated in many important biological processes such as transcription, recombination, DNA repair, and genome stability. These functions include the enhancement of binding of a number of transcription factors, including the tumor suppressor protein p53, to their specific DNA-binding sites. HMGB1 is composed of two highly conserved HMG boxes, linked to an intrinsically disordered acidic C-terminal tail. Previous reports have suggested that the ability of HMGB1 to bend DNA may explain the in vitro HMGB1-mediated increase in sequence-specific DNA binding by p53...
February 5, 2018: Biochimica et Biophysica Acta
Gehad Lotfy, El Sayed H El Ashry, Mohamed M Said, El Sayed El Tamany, Yasmine M Abdel Aziz, Abdullah Al-Dhfyan, Abdullah M Al-Majid, Assem Barakat
Owing to their structural novelty and inherent three-dimensionality, spiro scaffolds have been shown indisputable promise as chemopreventive agents. A new series of heterocycles containing spirooxindole and pyrrolidine rings were synthesized by the 1,3-dipolar cycloaddition of an azomethine ylide, which was generated in situ by the condensation of a secondary amino acid (l‑proline) and dicarbonyl compounds (isatin), with dipolarophiles. This method is simple and provides diverse and biologically interesting products...
January 31, 2018: Journal of Photochemistry and Photobiology. B, Biology
A Laroche-Clary, C Lucchesi, C Rey, S Verbeke, A Bourdon, V Chaire, M-P Algéo, S Cousin, M Toulmonde, V Vélasco, J Shutzman, A Savina, F Le Loarer, A Italiano
Background: Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1. Methods: We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy...
February 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Koji Kubota, Peng Dai, Bradley L Pentelute, Stephen L Buchwald
A new method for cysteine-lysine crosslinking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a crosslink. The linkage so formed is stable towards acid, base, oxygen and external thiol nucleophiles. This method was applied to crosslink cysteine with nearby lysines in sortase A*...
February 6, 2018: Journal of the American Chemical Society
Yucel Aydin, Animesh Chatterjee, Partha K Chandra, Srinivas Chava, Weina Chen, Anamika Tandon, Asha Dash, Milad Chedid, Martin W Moehlen, Frederic Regenstein, Luis A Balart, Ari Cohen, Hua Lu, Tong Wu, Srikanta Dash
The mechanism why hepatitis C virus (HCV) clearance by direct-acting antivirals (DAAs) does not eliminate the risk of hepatocellular carcinoma (HCC) among patients with advanced cirrhosis is unclear. Many viral and bacterial infections degrade p53 in favor of cell survival to adapt an endoplasmic reticulum (ER)-stress response. In this study, we examined whether HCV clearance by interferon-alpha or DAAs normalizes the ER stress and restores the expression of p53 tumor suppressor in cell culture. We found that HCV infection induces chronic ER stress and unfolded protein response in untransformed primary human hepatocytes...
May 2017: Hepatology Communications
Christopher D Wiley, Nicholas Schaum, Fatouma Alimirah, Jose Alberto Lopez-Dominguez, Arturo V Orjalo, Gary Scott, Pierre-Yves Desprez, Christopher Benz, Albert R Davalos, Judith Campisi
Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells...
February 5, 2018: Scientific Reports
Yongchao Zhao, Mingjia Tan, Xia Liu, Xiufang Xiong, Yi Sun
RPS27L (ribosomal protein S27-like) is an evolutionarily conserved ribosomal protein and a direct p53 target. We recently reported that Rps27l disruption triggers ribosomal stress to induce p53, causing postnatal death, which can be rescued by Trp53 +/- . Whether and how Rps27l modulates radiosensitivity is unknown. Here we report that Rps27l -/- ; Trp53 +/- mice are extremely sensitive to radiation due to reduced proliferation and massive induction of apoptosis in radiation-sensitive organs. Mechanistically, the radiation sensitivity is mediated by two signaling pathways: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) reduced DNA damage response due to reduced MRN/Atm signal as a result of elevated Mdm2 binding of Nbs1 to inhibit Nbs1-Atm binding and subsequent Atm activation...
February 2, 2018: Cell Death & Disease
Yalu Zhou, Ricardo E Perez, Lei Duan, Carl G Maki
MDM2 antagonists stabilize and activate wild-type p53, and histone methyltransferase (HMT) inhibitors reduce methylation on histone lysines and arginines. Both MDM2 antagonists and HMT inhibitors are being developed as cancer therapeutics. Wild-type p53 expressing HCT116 colon cancer cells were resistant to apoptosis in response to the MDM2 antagonist Nutlin-3a. However, co-treatment with the HMT inhibitor DZNep sensitized the cells to Nutlin-3a-induced apoptosis. This sensitization resulted from reduced activity of the Bcl-2 gene promoter and a reduction in Bcl-2 mRNA and protein...
February 2, 2018: Cancer Biology & Therapy
Lindi Chen, Arman Esfandiari, William Reaves, Annette Vu, Michael D Hogarty, John Lunec, Deborah A Tweddle
Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. In this study, the Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, western blot analysis and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) was determined using XTT proliferation assays...
January 31, 2018: International Journal of Oncology
Steven Blotner, Lin-Chi Chen, Cristiano Ferlini, Jianguo Zhi
PURPOSE: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval. METHOD: Intensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML...
February 1, 2018: Cancer Chemotherapy and Pharmacology
Jiang-Jiang Qin, Wei Wang, Xin Li, Hemantkumar Deokar, John K Buolamwini, Ruiwen Zhang
The β-catenin and MDM2 oncoproteins are overexpressed and constitutively activated in human pancreatic cancer and contribute to its initiation, progression, and metastasis. The Wnt/β-catenin signaling pathway strongly interacts with the MDM2-p53 signaling pathway, accelerating the tumorigenesis and its development. Therefore, therapies inhibiting both β-catenin and MDM2 are suggested to be ideal treatments for patients with advanced pancreatic cancer. We have recently identified a novel class of β-carboline compounds as the specific and potent MDM2 inhibitors, including a lead compound SP141...
2018: Frontiers in Pharmacology
Ilaria Moscetti, Anna Rita Bizzarri, Salvatore Cannistraro
p53 plays an important role in the safeguard of the genome but it is frequently downregulated mainly by E3 ubiquitin ligases among which COP1 plays an important role. The overexpression of COP1 has been reported to occur in several tumors and may be indicative of its overall oncogenic effect, which in turn might be originated by a direct interaction of COP1 with p53. Such an interaction may constitute a rewarding target for anticancer drug design strategies; therefore, a deeper understanding of its underlying molecular mechanism and kinetics is needed...
2018: International Journal of Nanomedicine
Rebeca Vecino, Maria C Burguete, Teresa Jover-Mengual, Jesus Agulla, Verónica Bobo-Jiménez, Juan B Salom, Angeles Almeida, Maria Delgado-Esteban
Brain preconditioning (PC) refers to a state of transient tolerance against a lethal insult that can be evoked by a prior mild event. It is thought that PC may induce different pathways responsible for neuroprotection, which may involve the attenuation of cell damage pathways, including the apoptotic cell death. In this context, p53 is a stress sensor that accumulates during brain ischemia leading to neuronal death. The murine double minute 2 gene (MDM2), a p53-specific E3 ubiquitin ligase, is the main cellular antagonist of p53, mediating its degradation by the proteasome...
January 25, 2018: Scientific Reports
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