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p53 mdm2

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https://www.readbyqxmd.com/read/28811661/myst2-kat7-histone-acetyltransferase-interaction-proteomics-reveals-tumour-suppressor-niam-as-a-novel-binding-partner-in-embryonic-stem-cells
#1
Mercedes Pardo, Lu Yu, Shihpei Shen, Peri Tate, Daniel Bode, Blake L Letney, Dawn E Quelle, William Skarnes, Jyoti S Choudhary
MYST histone acetyltransferases have crucial functions in transcription, replication and DNA repair and are hence implicated in development and cancer. Here we characterise Myst2/Kat7/Hbo1 protein interactions in mouse embryonic stem cells by affinity purification coupled to mass spectrometry. This study confirms that in embryonic stem cells Myst2 is part of H3 and H4 histone acetylation complexes similar to those described in somatic cells. We identify a novel Myst2-associated protein, the tumour suppressor protein Niam (Nuclear Interactor of ARF and Mdm2)...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807825/usp3-stabilizes-p53-protein-through-its-deubiquitinase-activity
#2
Song Fu, Shize Shao, Longqiang Wang, Haijun Liu, Haitao Hou, Yanan Wang, Huan Wang, Xiangpeng Huang, Renhua Lv
p53 is the guardian of the genome integrity and the degradation of p53 protein is mediated by MDM2. Here we report that USP3 interacts with p53 and regulates p53 stability. Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. These findings suggest that USP3 is an important regulator of p53 and regulates normal cell transformation...
August 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28806397/mdm2-promotes-cdc25c-protein-degradation-and-delays-cell-cycle-progression-through-the-g2-m-phase
#3
L E Giono, L Resnick-Silverman, L A Carvajal, S St Clair, J J Manfredi
Upon different types of stress, the gene encoding the mitosis-promoting phosphatase Cdc25C is transcriptionally repressed by p53, contributing to p53's enforcement of a G2 cell cycle arrest. In addition, Cdc25C protein stability is also decreased following DNA damage. Mdm2, another p53 target gene, encodes a ubiquitin ligase that negatively regulates p53 levels by ubiquitination. Ablation of Mdm2 by siRNA led to an increase in p53 protein and repression of Cdc25C gene expression. However, Cdc25C protein levels were actually increased following Mdm2 depletion...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28802167/induction-of-senescence-in-cancer-cells-by-5-aza-2-deoxycytidine-bioinformatics-and-experimental-insights-to-its-targets
#4
Jayarani F Putri, Nashi Widodo, Kazuichi Sakamoto, Sunil C Kaul, Renu Wadhwa
5'-Aza-2'-deoxycytidine (5-Aza-dC) is a demethylating drug that causes genome-wide hypomethylation resulting in the expression of several tumor suppressor genes causing growth arrest of cancer cells. Cancer is well established as a multifactorial disease and requires multi-module therapeutics. Search for new drugs and their approval by FDA takes a long time. Keeping this in view, research on new functions of FDA-approved anticancer drugs is desired to expand the list of multi-module functioning drugs for cancer therapy...
August 2, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28800790/mir-641-functions-as-a-tumor-suppressor-by-targeting-mdm2-in-human-lung-cancer
#5
Qinglong Kong, Nan Shu, Jun Li, Ning Xu
Lung cancer is the leading cause of deaths due to cancer. Studies suggest important role of microRNAs (miRNAs) in a variety of cancer, including lung cancer. In the present study, we evaluated the role of miR-641 in human lung cancer A549 cells. Quantitative RT-PCR and Western blot was used to measure the mRNA and protein expression, respectively. Cell viability and cell apoptosis were respectively measured by MTT assay and flow cytometry. Besides, luciferase activity assay was used to identify the target of miR-641...
August 11, 2017: Oncology Research
https://www.readbyqxmd.com/read/28800455/in%C3%A2-vitro-targeting-of-colon-cancer-cells-using-spiropyrazoline-oxindoles
#6
Rute C Nunes, Carlos J A Ribeiro, Ângelo Monteiro, Cecília M P Rodrigues, Joana D Amaral, Maria M M Santos
We report on the synthesis and biological evaluation of a library of twenty-three spiropyrazoline oxindoles. The antiproliferative activity of the chemical library was evaluated in HCT-116 p53((+/+)) human colon cancer cell line with eight derivatives displaying good activities (IC50<15 μM). To characterize the molecular mechanisms involved in compound antitumoral activity, two spiropyrazoline oxindoles were selected for further studies. Both compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase and upregulated p53 steady-state levels, while decreasing its main inhibitor MDM2...
July 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28798142/accumulation-of-smooth-muscle-22%C3%AE-protein-accelerates-senescence-of-vascular-smooth-muscle-cells-via-stabilization-of-p53-in-vitro-and-in-vivo
#7
Sui-Bing Miao, Xiao-Li Xie, Ya-Juan Yin, Li-Li Zhao, Fan Zhang, Ya-Nan Shu, Rong Chen, Peng Chen, Li-Hua Dong, Yan-Ling Lin, Pin Lv, Dan-Dan Zhang, Xi Nie, Zhen-Ying Xue, Mei Han
OBJECTIVE: Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment...
August 10, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28797774/design-synthesis-and-biological-evaluation-of-novel-antitumor-spirotetrahydrothiopyran-oxindole-derivatives-as-potent-p53-mdm2-inhibitors
#8
Changjin Ji, Shengzheng Wang, Shuqiang Chen, Shipeng He, Yan Jiang, Zhenyuan Miao, Jian Li, Chunquan Sheng
p53-MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran-oxindole p53-MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships. Among them, compound B14 bearing a novel spiroindole-thiopyranopyridone scaffold exhibited potent MDM2 inhibitory activity as well as antitumor activity, which could effectively induce the apoptosis of A549 cancer cells...
July 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28774266/evolution-of-the-p53-mdm2-pathway
#9
Emma Åberg, Fulvio Saccoccia, Manfred Grabherr, Wai Ying Josefin Ore, Per Jemth, Greta Hultqvist
BACKGROUND: The p53 signalling pathway, which controls cell fate, has been extensively studied due to its prominent role in tumor development. The pathway includes the tumor supressor protein p53, its vertebrate paralogs p63 and p73, and their negative regulators MDM2 and MDM4. The p53/p63/p73-MDM system is ancient and can be traced in all extant animal phyla. Despite this, correct phylogenetic trees including both vertebrate and invertebrate species of the p53/p63/p73 and MDM families have not been published...
August 3, 2017: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28766941/a-computational-investigation-of-small-molecule-engagement-of-hot-spots-at-protein-protein-interaction-interfaces
#10
David Xu, Yubing Si, Samy O Meroueh
The binding affinity of a protein-protein interaction is concentrated at amino acids known as hot spots. It has been suggested that small molecules disrupt protein-protein interactions by either (i) engaging receptor protein hot spots; or (ii) mimicking hot spots of the protein ligand. Yet, to date, no systematic studies have been done to explore how effectively existing small-molecule protein-protein interaction inhibitors mimic or engage hot spots at protein interfaces. Here, we employ explicit-solvent molecular dynamics simulations and end-point MM-GBSA free energy calculations to explore this question...
August 2, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28765552/antitumoral-effects-of-%C3%AE-cdcpli-a-pla2-inhibitor-from-crotalus-durissus-collilineatus-via-pi3k-akt-pathway-on-mda-mb-231-breast-cancer-cell
#11
Sarah N C Gimenes, Daiana S Lopes, Patrícia T Alves, Fernanda V P V Azevedo, Lara Vecchi, Luiz R Goulart, Thais C S Rodrigues, André L Q Santos, Vera L de C Brites, Thaise L Teixeira, Cláudio V da Silva, Matheus H Dias, Samuel C Teixeira, Renata S Rodrigues, Kelly A G Yoneyama, Ricardo A Oliveira, Veridiana de M Rodrigues
Phospholipases A2 (PLA2s) overexpression is closely associated with the malignant potential of breast cancers. Here, we showed for the first the antitumoral effects of γCdcPLI, a PLA2 inhibitor from Crotalus durissus collilineatus via PI3K/Akt pathway on MDA-MB-231 cell. Firstly, γCdcPLI was more cytotoxic to MDA-MB-231 breast cancer cells than other cell lines (MCF-7, HeLa, PC3 and A549) and did not affect the viability of non-tumorigenic breast cell (MCF 10A). In addition, γCdcPLI induced modulation of important mediators of apoptosis pathways such as p53, MAPK-ERK, BIRC5 and MDM2...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28762569/gabp%C3%AE-is-involved-in-the-survival-of-mouse-embryonic-stem-cells
#12
Atsushi Ueda, Tadayuki Akagi, Takashi Yokota
Ets-related transcription factor GA-binding protein alpha (GABPα), which is encoded by Gabpa, is expressed in a variety of cell types and is involved in cellular functions such as cell cycle regulation, apoptosis, and differentiation. Here we generated Gabpa conditional knockout embryonic stem (ES) cells and characterized its cellular phenotypes. Disruption of Gabpa revealed that the proliferation of Gabpa-null ES cells was drastically repressed and cells started to die within 2 days. The repressed proliferation of Gabpa-null ES cells was recovered by artificially forced expression of GABPα...
August 1, 2017: Stem Cells
https://www.readbyqxmd.com/read/28756477/p53-signaling-pathway-polymorphisms-cancer-risk-and-tumor-phenotype-in-tp53-r337h-mutation-carriers
#13
Gabriel S Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Juliana Giacomazzi, Ana Paula Carneiro Brandalize, Maira Caleffi, Sahlua Miguel Volc, Henrique de Campos Reis Galvão, Edenir Inez Palmero, Maria Isabel Achatz, Patricia Ashton-Prolla
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186)...
July 29, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28754870/combination-treatment-with-rucaparib-rubraca-and-mdm2-inhibitors-nutlin-3-and-rg7388-has-synergistic-and-dose-reduction-potential-in-ovarian-cancer
#14
Maryam Zanjirband, Nicola Curtin, Richard J Edmondson, John Lunec
Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials...
July 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28749206/small-molecule-cb002-restores-p53-pathway-signaling-and-represses-colorectal-cancer-cell-growth
#15
Colby Richardson, Shengliang Zhang, Liz J Hernandez Borrero, Wafik S El-Deiry
Much effort is currently focused on the p53 pathway. p53 is a key tumor suppressor, which is mutated or lost in many human cancers. Restoration of the p53 pathway holds the potential to induce selective cell death in tumor cells without harming normal cells that have intact p53 pathways. Most tumor cells express mutated p53 or suppress p53 by overexpression of MDM2. In this study, a compound referred to as CB002 with one closely related compound from the Chembridge library were evaluated for tumor cytotoxicity without affecting normal cells by restoration of the p53 pathway...
July 27, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28746345/cisplatin-resistance-in-non-small-cell-lung-cancer-cells-is-associated-with-an-abrogation-of-cisplatin-induced-g2-m-cell-cycle-arrest
#16
Navin Sarin, Florian Engel, Ganna V Kalayda, Mareike Mannewitz, Jindrich Cinatl, Florian Rothweiler, Martin Michaelis, Hisham Saafan, Christoph A Ritter, Ulrich Jaehde, Roland Frötschl
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response...
2017: PloS One
https://www.readbyqxmd.com/read/28745540/p53-and-mdm2-act-synergistically-to-maintain-cardiac-homeostasis-and-mediate-cardiomyocyte-cell-cycle-arrest-through-a-network-of-micrornas
#17
Shanna Stanley-Hasnain, Ludger Hauck, Daniela Grothe, Roozbeh Aschar-Sobbi, Sanja Beca, Jagdish Butany, Peter H Backx, Tak W Mak, Filio Billia
Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy...
July 26, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28741501/retinoblastoma-binding-protein-6-another-p53-monitor
#18
Monde Ntwasa
The retinoblastoma binding protein 6 (RBBP6), a p53 negative regulator, is essential for embryonic development. Its loss-of-function phenotype is similar to mouse double minute homolog (MDM2), the prototypical negative regulator of p53. This article draws attention to the molecular and biological functions of RBBP6 and to its association with carcinogenesis.
November 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28732184/high-throughput-identification-of-mir-596-inducing-p53-mediated-apoptosis-in-hela-and-hct116-cells-using-cell-microarray
#19
Ming Ma, Junyu Yang, Bolun Wang, Zhihua Zhao, Jianzhong Jeff Xi
miRNAs play a key role in the regulation of gene networks in mammalian cells. However, little is known about their roles and functions in the apoptosis pathway. Here, we conducted a whole-genome miRNA screening for apoptosis and identified more than 100 miRNAs as apoptosis inducers. To further explain the roles of these mRNAs in apoptosis, a second round of screening was conducted between p53 +/+ and -/- cells. Among the hits, miR-596 was identified as a regulator of p53. The overexpression of miR-596 significantly increased p53 at the protein level, thereby inducing apoptosis...
July 1, 2017: SLAS Technology
https://www.readbyqxmd.com/read/28723868/screening-of-medicinal-plant-phytochemicals-as-natural-antagonists-of-p53-mdm2-interaction-to-reactivate-p53-functioning
#20
Muhammad Riaz, Usman A Ashfaq, Muhammad Qasim, Erum Yasmeen, Muhammad T Ul Qamar, Farooq Anwar
In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. The crystal structure of MDM2, with a 109-residue amino-terminal domain, reveals that MDM2 has a core hydrophobic region to which p53 binds as an amphipathic α helix. The interface depends on the steric complementarity between MDM2 and the hydrophobic region of p53. Especially, on p53's triad, amino acids Phe19, Trp23 and Leu26 bind to the MDM2 core. Results from studies suggest that the structural motif of both p53 and MDM2 can be attributed to similarities in the amphipathic α helix...
July 18, 2017: Anti-cancer Drugs
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