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p53 mdm2

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https://www.readbyqxmd.com/read/29242407/central-role-of-the-p53-pathway-in-the-noncoding-rna-response-to-oxidative-stress
#1
Paola Fuschi, Matteo Carrara, Christine Voellenkle, Jose Manuel Garcia-Manteiga, Paolo Righini, Biagina Maimone, Elena Sangalli, Francesco Villa, Claudia Specchia, Mario Picozza, Giovanni Nano, Carlo Gaetano, Gaia Spinetti, Annibale A Puca, Alessandra Magenta, Fabio Martelli
Oxidative stress plays a fundamental role in many conditions. Specifically, redox imbalance inhibits endothelial cell (EC) growth, inducing cell death and senescence. We used global transcriptome profiling to investigate the involvement of noncoding-RNAs in these phenotypes. By RNA-sequencing, transcriptome changes were analyzed in human ECs exposed to H2O2, highlighting a pivotal role of p53-signaling. Bioinformatic analysis and validation in p53-silenced ECs, identified several p53-targets among both mRNAs and long noncoding-RNAs (lncRNAs), including MALAT1 and NEAT1...
December 12, 2017: Aging
https://www.readbyqxmd.com/read/29235570/targeting-negative-regulation-of-p53-by-mdm2-and-wip1-as-a-therapeutic-strategy-in-cutaneous-melanoma
#2
Chiao-En Wu, Arman Esfandiari, Yi-Hsuan Ho, Nan Wang, Ahmed Khairallah Mahdi, Erhan Aptullahoglu, Penny Lovat, John Lunec
BACKGROUND: Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells...
December 12, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/29233996/pepd-is-a-pivotal-regulator-of-p53-tumor-suppressor
#3
Lu Yang, Yun Li, Arup Bhattacharya, Yuesheng Zhang
p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29228061/structure-activity-studies-of-mdm2-mdm4-binding-stapled-peptides-comprising-non-natural-amino-acids
#4
Sharon Min Qi Chee, Jantana Wongsantichon, Jiawei Siau, Dawn Thean, Fernando Ferrer, Robert C Robinson, David P Lane, Christopher J Brown, Farid J Ghadessy
As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6-chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1...
2017: PloS One
https://www.readbyqxmd.com/read/29211796/reprogramming-pancreatic-stellate-cells-via-p53-activation-a-putative-target-for-pancreatic-cancer-therapy
#5
Maya Saison-Ridinger, Kathleen E DelGiorno, Tejia Zhang, Annabelle Kraus, Randall French, Dawn Jaquish, Crystal Tsui, Galina Erikson, Benjamin T Spike, Maxim N Shokhirev, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Alan Saghatelian, Andrew M Lowy, Geoffrey M Wahl
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, cell cycle arrest, and senescence...
2017: PloS One
https://www.readbyqxmd.com/read/29210587/organocatalytic-asymmetric-synthesis-of-spiro-oxindole-piperidine-derivatives-that-reduce-cancer-cell-proliferation-by-inhibiting-mdm2-p53-interaction
#6
Ming-Cheng Yang, Cheng Peng, Hua Huang, Lei Yang, Xiang-Hong He, Wei Huang, Hai-Lei Cui, Gu He, Bo Han
Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibited the proliferation of several breast cancer cell lines. Mechanistic studies suggest that the most potent compound 9e can directly interfere with MDM2-p53 interactions and elevate protein levels of p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis...
December 6, 2017: Organic Letters
https://www.readbyqxmd.com/read/29207594/cancer-mutated-ribosome-protein-l22-rpl22-el22-suppresses-cancer-cell-survival-by-blocking-p53-mdm2-circuit
#7
Bo Cao, Ziling Fang, Peng Liao, Xiang Zhou, Jianping Xiong, Shelya Zeng, Hua Lu
Several ribosomal proteins (RPs) in response to various ribosomal stressors have been shown to play a critical role in p53-dependent regulation of cell cycle arrest, apoptosis and tumor suppression. Here, we report ribosomal protein L22 (RPL22/eL22) as a novel p53 activator highly mutated (mostly deletion mutation) in various types of human cancers, but not essential for ribosomal biogenesis in normal cells. Ectopic expression of RPL22/eL22 suppressed the colony formation of cancer cells in a p53-dependent manner, whereas knockdown of RPL22/eL22 significantly compromised p53 activation by Actinomycin D, rescuing p53-induced G1/G0 cell cycle arrest...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207130/ethanol-extract-from-cnidium-monnieri-l-cusson-induces-cell-cycle-arrest-and-apoptosis-via-regulation-of-the-p53%C3%A2-independent-pathway-in-hepg2-and-hep3b-hepatocellular-carcinoma-cells
#8
Eun Gyeong Lim, Guen Tae Kim, Bo Min Kim, Eun Ji Kim, Sang-Yong Kim, Young Min Kim
Cnidium monnieri (L.) Cusson is a frequently used traditional Chinese medicine that treats gynecological diseases and carbuncles. However, the mechanism of action of C. monnieri remains to be fully elucidated. The present study examined the cell cycle arrest and apoptotic effects resulting from ethanol extract of C. monnieri (CME) in HepG2 (wild‑type p53) and Hep3B (p53‑null) hepatocellular carcinoma cells. An MTT assay was used to confirm the anti‑proliferative effect of CME. The cells were stained with Hoechst 33342 or propidium iodide...
November 29, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29193730/the-3p14-2-tumour-suppressor-adamts9-is-inactivated-by-promoter-cpg-methylation-and-inhibits-tumour-cell-growth-in-breast-cancer
#9
Bianfei Shao, Yixiao Feng, Hongbin Zhang, Fang Yu, Qianqian Li, Cui Tan, Hongying Xu, Jianming Ying, Lili Li, Dejuan Yang, Weiyan Peng, Jun Tang, Shuman Li, Guosheng Ren, Qian Tao, Tingxiu Xiang
Chromosome region 3p12-14 is an important tumour suppressor gene (TSG) locus for multiple cancers. ADAMTS9, a member of the metalloprotease large family, has been identified as a candidate 3p14.2 TSG inactivated by aberrant promoter CpG methylation in several carcinomas, but little known about its expression and function in breast cancer. In this report, ADAMTS9 expression and methylation was analysed in breast cancer cell lines and tissue samples. ADAMTS9 RNA was significantly down-regulated in breast cancer cell lines (6/8)...
November 29, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29193479/bcl-xl-binds-and-antagonizes-rassf6-tumor-suppressor-to-suppress-p53-expression
#10
Xiaoyin Xu, Hiroaki Iwasa, Shakhawoat Hossain, Aradhan Sarkar, Junichi Maruyama, Kyoko Arimoto-Matsuzaki, Yutaka Hata
RASSF6, a member of the tumor suppressor Ras-association domain family proteins, induces apoptosis in the caspase-dependent and caspase-independent manners. RASSF6 interacts with MDM2 and stabilizes p53. BCL-XL is a prosurvival member of BCL-2 family proteins. BCL-XL directly inhibits proapoptotic BAX and BAK. BCL-XL also traps tBID, a proapoptotic activator BH3-only protein, and sequesters p53. In addition, BCL-XL regulates the mitochondrial membrane permeability via voltage-dependent anion channel. In these manners, BCL-XL plays an antiapoptotic role...
November 28, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/29192902/relevance-of-the-p53-mdm2-axis-to-aging
#11
REVIEW
Danyi Wu, Carol Prives
In response to varying stress signals, the p53 tumor suppressor is able to promote repair, survival, or elimination of damaged cells - processes that have great relevance to organismal aging. Although the link between p53 and cancer is well established, the contribution of p53 to the aging process is less clear. Delineating how p53 regulates distinct aging hallmarks such as cellular senescence, genomic instability, mitochondrial dysfunction, and altered metabolic pathways will be critical. Mouse models have further revealed the centrality and complexity of the p53 network in aging processes...
December 1, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29190376/p53-promotes-akt-and-sp1-dependent-metabolism-through-the-pentose-phosphate-pathway-that-inhibits-apoptosis-in-response-to-nutlin-3a
#12
Lei Duan, Ricardo E Perez, Ling Chen, Lothar A Blatter, Carl G Maki
Nutlin-3a is a MDM2 antagonist and preclinical drug that activates p53. Cells with MDM2 gene amplification are especially prone to Nutlin-3a-induced apoptosis, though the basis for this is unclear. Glucose metabolism can inhibit apoptosis in response to Nutlin-3a through mechanisms that are incompletely understood. Glucose metabolism through the pentose phosphate pathway (PPP) produces NADPH that can protect cells from potentially lethal reactive oxygen species (ROS). We compared apoptosis and glucose metabolism in cancer cells with and without MDM2 gene amplification treated with Nutlin-3a...
November 27, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29181159/investigation-of-the-association-between-the-mdm2-t309g-polymorphism-and-gastric-cancer
#13
Ayca Tas, Mustafa Atabey, Gulcin Caglayan, Meric Emre Bostanci, Serap Sahin Bolukbasi, Omer Topcu, Yavuz Silig
Murine double minute clone 2 oncoprotein (MDM2) is a key component in the regulation of the tumour suppressor p53. The association between the MDM2 polymorphism and gastric cancer (GC) has been investigated in Turkish population. In the present case-control study, the aim was to investigate the association between genetic polymorphisms of the MDM2 gene (a major regulator of p53 function) and primary GC risk in a Turkish population. The polymorphism, T309G (rs2279744) in the MDM2 gene was determined in patients with GC (n=65) and in healthy control subjects (n=67) using the polymerase chain reaction-restriction fragment length polymorphism method...
November 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29179447/the-tumor-suppressor-rassf1a-induces-the-yap1-target-gene-ankrd1-that-is-epigenetically-inactivated-in-human-cancers-and-inhibits-tumor-growth
#14
Adriana P Jiménez, Annalena Traum, Thomas Boettger, Holger Hackstein, Antje M Richter, Reinhard H Dammann
The Hippo pathway regulates organ size, growth and comprises several tumor related factors, including the oncoprotein YAP1 and the tumor suppressor RASSF1A. RASSF1A is frequently epigenetically inactivated in cancer. In our study, we analyzed the effect of RASSF1A on the function of YAP1. Expression of YAP1 resulted in the downregulation of several tumor suppressor genes and induction of S-phase. Co-expression with RASSF1A normalized the expression levels of these tumor suppressors and induced a G0-G1 arrest and apoptosis...
October 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/29175211/nutlin-sensitizes-lung-carcinoma-cells-to-interferon-alpha-treatment-in-mdm2-dependent-but-p53-independent-manner
#15
Oleg Shuvalov, Alena Kizenko, Ajgul Shakirova, Olga Fedorova, Alexey Petukhov, Nikolai Aksenov, Elena Vasileva, Alexandra Daks, Nickolai Barlev
As an anticancer therapeutic, Interferon-alpha (IFNα) is used to treat a number of malignancies. However, the application of IFNα is restricted mostly due to its high toxicity. Therefore, novel combination therapeutic regimens are required to decrease the toxicity of IFNα and enhance its efficacy. Here we show that the treatment of p53-deficient human non-small lung carcinoma H1299 cells with IFNα in combination with an inhibitor of MDM2, Nutlin-3a, synergistically affects the proliferation of cancer cells...
November 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29168185/yy1-suppresses-proliferation-and-migration-of-pancreatic-ductal-adenocarcinoma-by-regulating-the-cdkn3-mdm2-p53-p21-signaling-pathway
#16
Dongfang Liu, Jingjing Zhang, Yang Wu, Guodong Shi, Hao Yuan, Zipeng Lu, Qicong Zhu, Pengfei Wu, Cheng Lu, Feng Guo, Jianmin Chen, Kuirong Jiang, Yi Miao
Pancreatic ductal adenocarcinoma (PDAC) is one of the malignant lethal tumors. It has been reported that the transcriptional regulator Yin Yang-1 (YY1) suppressed the invasion and metastasis of PDAC. However, the function of YY1 on proliferation and migration of pancreatic cancer remains to be clarified. In this study, we found that YY1 overexpression or knockdown can inhibit or promote the proliferation and migration of pancreatic cancer cells. Digital gene expression (DGE) sequencing indicates that cyclin-dependent kinase inhibitor 3 (CDKN3) may be the candidate target gene of YY1...
November 23, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29158845/in-tether-chiral-center-induced-helical-peptide-modulators-target-p53-mdm2-mdmx-and-inhibit-tumor-growth-in-stem-like-cancer-cell
#17
Kuan Hu, Feng Yin, Mengyin Yu, Chengjie Sun, Jingxu Li, Yujie Liang, Wenjun Li, Mingsheng Xie, Yuanzhi Lao, Wei Liang, Zi-Gang Li
Inhibition of the interaction between p53 and MDM2/MDMX has attracted significant attention in anticancer therapy development. We designed a series of in-tether chiral center-induced helical stabilized peptides, among which MeR/PhR effectively reactivated p53. The activation of p53 inhibits cell proliferation and induces apoptosis in both the MCF-7 normal tumor cell line and the PA-1 pluripotent cancer cell line with only minimal cellular toxicity towards normal cells or cancer cell lines with p53 mutations...
2017: Theranostics
https://www.readbyqxmd.com/read/29156828/the-%C3%AE-glucan-from-lentinus-edodes-suppresses-cell-proliferation-and-promotes-apoptosis-in-estrogen-receptor-positive-breast-cancers
#18
Hui Xu, Siwei Zou, Xiaojuan Xu
Breast cancer is now the most common cancer in worldwide women, and novel interventions are needed to overcome the resistance occurring in the estrogen-targeted endocrine therapy. Herein, we demonstrate that the β-glucan from Lentinus edodes (LNT) exhibited a profound inhibition ratio of ∼53% against estrogen receptor positive (ER+) MCF-7 tumor growth in nude mice similar to the positive control of cisplatin. Immunohistochemistry images showed that LNT evidently suppressed cell proliferation and promoted apoptosis in MCF-7 tumor tissues...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156743/hepatitis-c-virus-core-overcomes-all-trans-retinoic-acid-induced-apoptosis-in-human-hepatoma-cells-by-inhibiting-p14-expression-via-dna-methylation
#19
Juri Kwak, Jung-Hye Choi, Kyung Lib Jang
All-trans retinoic acid (ATRA), the most biologically active metabolite of vitamin A, is known to induce p14 expression via promoter hypomethylation to activate the p14-MDM2-p53 pathway, which leads to activation of the p53-dependent apoptotic pathway and subsequent induction of apoptosis in human hepatoma cells. In the present study, we found that hepatitis C virus (HCV) Core derived from ectopic expression or HCV infection overcomes ATRA-induced apoptosis in p53-positive hepatoma cells. For this effect, HCV Core upregulated both protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b and thereby repressed p14 expression via promoter hypermethylation, resulting in inactivation of the pathway leading to p53 accumulation in the presence of ATRA...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29153842/stress-activated-nrf2-mdm2-cascade-controls-neoplastic-progression-in-pancreas
#20
Jelena Todoric, Laura Antonucci, Giuseppe Di Caro, Ning Li, Xuefeng Wu, Nikki K Lytle, Debanjan Dhar, Sourav Banerjee, Johan B Fagman, Cecille D Browne, Atsushi Umemura, Mark A Valasek, Hannes Kessler, David Tarin, Michael Goggins, Tannishtha Reya, Maria Diaz-Meco, Jorge Moscat, Michael Karin
Despite expression of oncogenic KRAS, premalignant pancreatic intraepithelial neoplasia 1 (PanIN1) lesions rarely become fully malignant pancreatic ductal adenocarcinoma (PDAC). The molecular mechanisms through which established risk factors, such as chronic pancreatitis, acinar cell damage, and/or defective autophagy increase the likelihood of PDAC development are poorly understood. We show that accumulation of the autophagy substrate p62/SQSTM1 in stressed Kras(G12D) acinar cells is associated with PDAC development and maintenance of malignancy in human cells and mice...
November 7, 2017: Cancer Cell
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