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https://www.readbyqxmd.com/read/28092675/unbalancing-p53-mdm2-igf-1r-axis-by-mdm2-activation-restrains-the-igf-1-dependent-invasive-phenotype-of-skin-melanoma
#1
C Worrall, N Suleymanova, C Crudden, I Trocoli Drakensjö, E Candrea, D Nedelcu, S-I Takahashi, L Girnita, A Girnita
Melanoma tumors usually retain wild-type p53; however, its tumor-suppressor activity is functionally disabled, most commonly through an inactivating interaction with mouse double-minute 2 homolog (Mdm2), indicating p53 release from this complex as a potential therapeutic approach. P53 and the tumor-promoter insulin-like growth factor type 1 receptor (IGF-1R) compete as substrates for the E3 ubiquitin ligase Mdm2, making their relative abundance intricately linked. Hence we investigated the effects of pharmacological Mdm2 release from the Mdm2/p53 complex on the expression and function of the IGF-1R...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/28088193/invasive-cardiac-lipoma-a-case-report-and-review-of-literature
#2
Jason D'Souza, Rajesh Shah, Aamer Abbass, Jeremy R Burt, Aditya Goud, Chanukya Dahagam
BACKGROUND: Cardiac lipomas are rare benign tumors of the heart. They are usually asymptomatic and are thus most often diagnosed on autopsies. Symptoms, when present, depend upon the location within the heart. Typical locations are the endocardium of the right atrium and the left ventricle. Diagnostic modality of choice is cardiac MRI. Treatment guidelines have not yet been established due to the very low prevalence of these tumors and are thus guided by the patient's symptomatology. CASE PRESENTATION: We describe a case of an invasive cardiac lipoma, wherein the initial symptom of the patient was shortness of breath...
January 14, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28077607/anatomy-of-mdm2-and-mdm4-in-evolution
#3
REVIEW
Ban Xiong Tan, Hoe Peng Liew, Joy S Chua, Farid J Ghadessy, Yaw Sing Tan, David P Lane, Cynthia R Coffill
Mouse double minute (Mdm) genes span an evolutionary timeframe from the ancient eukaryotic placozoa Trichoplax adhaerens to Homo sapiens, implying a significant and possibly conserved cellular role throughout history. Maintenance of DNA integrity and response to DNA damage involve many key regulatory pathways, including precise control over the tumour suppressor protein p53. In most vertebrates, degradation of p53 through proteasomal targeting is primarily mediated by heterodimers of Mdm2 and the Mdm2-related protein Mdm4 (also known as MdmX)...
January 10, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28073006/bcl9l-dysfunction-impairs-caspase-2-expression-permitting-aneuploidy-tolerance-in-colorectal-cancer
#4
Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling...
January 9, 2017: Cancer Cell
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
#5
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/28070015/inhaled-resveratrol-treatments-slow-ageing-related-degenerative-changes-in-mouse-lung
#6
Barbara Driscoll, Sonia Navarro, Raghava Reddy, Jooeun Lee, David Warburton
BACKGROUND: Lung ageing, a significant risk factor for chronic human lung diseases such as COPD and emphysema, is characterised by airspace enlargement and decreasing lung function. Likewise, in prematurely ageing telomerase null (terc-/-) mice, p53 stabilisation within diminishing numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced lung function. Resveratrol (RSL) is a plant phytoalexin that has previously showed efficacy in enhancing invertebrate longevity and supporting mammalian muscle metabolism when delivered orally...
January 9, 2017: Thorax
https://www.readbyqxmd.com/read/28069666/negative-auto-regulators-trap-p53-in-their-web
#7
REVIEW
Xiang Zhou, Bo Cao, Hua Lu
The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signaling network, resulting in various cellular outcomes, such as growth arrest, senescence, apoptosis, and metabolic changes, and leading to consequent suppression of tumor growth and progression. Because of the profoundly adverse effect of p53 on growth and proliferation of cancer cells, several feedback mechanisms have been employed by the cells to constrain p53 activity. Two major antagonists MDM2 and MDMX (the long forms) are transcriptionally induced by p53, but in return block p53 activity, forming a negative feedback circuit and rendering chemoresistance of several cancer cells...
January 9, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28068628/epoxy-clerodane-diterpene-inhibits-mcf-7-human-breast-cancer-cell-growth-by-regulating-the-expression-of-the-functional-apoptotic-genes-cdkn2a-rb1-mdm2-and-p53
#8
P Subash-Babu, Ghedeir M Alshammari, S Ignacimuthu, Ali A Alshatwi
Systematic analyses of plants that are used in traditional medicine may lead to the discovery of novel cytotoxic secondary metabolites. Diterpene possesses multiple bioactivities; here, epoxy clerodane diterpene (ECD) was isolated from Tinospora cordifolia (Willd.) stem and shown potential antiproliferative effect in MCF-7 human breast cancer cells. The antiproliferative effect of ECD on MCF-7 cells was systematically analyzed by cell and nuclear morphology, alterations in oxidative stress, and the expression of tumor suppressor and mitochondria-mediated apoptosis-related genes...
January 6, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28064317/-b7-h4-mediated-immunoresistance-is-supressed-by-pi3k-akt-mtor-pathway-inhibitors
#9
S Zeng, H Song, Y Chen, W Xie, L Zhang
B7-H4 plays an important role in tumor immune evasion. In previous studies we have found that B7-H4 can translocate to the nucleus, and the exposure to PI3K inhibitor Ly294002 affects B7-H4 subcellular distribution. In this study we report the role of PI3K/Akt pathway in the B7-H4 subcellular distribution and the effect of PI3K/Akt inhibitors on B7-H4-mediated immunoresistance. The involvement of PI3K/Akt pathway in B7-H4 subcellular distribution was evident in experiments with wortmannin, while MDM2 inhibitor nutlin-3 and the mTOR inhibitor rapamycin were used to dissect the signaling downstream of Akt...
November 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28063307/sharpin-facilitates-p53-degradation-in-breast-cancer-cells
#10
Huijie Yang, Sifan Yu, Weilong Wang, Xin Li, Yingxiang Hou, Zhenhua Liu, Yuanyuan Shi, Kun Mu, Gang Niu, Juntao Xu, Hui Wang, Jian Zhu, Ting Zhuang
The ubiquitin binding protein SHAPRIN is highly expressed in human breast cancer, one of the most frequent female malignancies worldwide. Here, we perform SHARPIN depletion in breast cancer cells together with RNA sequencing. The global expression profiling showed p53 signaling as a potential SHARPIN target. SHARPIN depletion decreased cell proliferation, which effect could be rescue by p53 knocking down. Depletion SHARPIN significantly increases p53 protein level and its target genes in multiple breast cancer cell lines...
January 4, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28059589/an-hp1-isoform-specific-feedback-mechanism-regulates-suv39h1-activity-under-stress-conditions
#11
Helena Raurell-Vila, Laia Bosch-Presegue, Jessica Gonzalez, Noriko Kane-Goldsmith, Carmen Casal, Jeremy P Brown, Anna Marazuela-Duque, Prim B Singh, Lourdes Serrano, Alejandro Vaquero
The presence of H3K9me3 and heterochromatin protein 1 (HP1) are hallmarks of heterochromatin conserved in eukaryotes. The spreading and maintenance of H3K9me3 is effected by the functional interplay between the H3K9me3-specific histone methyltransferase Suv39h1 and HP1. This interplay is complex in mammals because the three HP1 isoforms, HP1α, β, and γ, are thought to play a redundant role in Suv39h1-dependent deposition of H3K9me3 in pericentric heterochromatin (PCH). Here, we demonstrate that despite this redundancy, HP1α and, to a lesser extent, HP1γ have a closer functional link to Suv39h1, compared to HP1β...
January 6, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28052121/molecular-characteristics-of-high-dose-melphalan-associated-oral-mucositis-in-patients-with-multiple-myeloma-a-gene-expression-study-on-human-mucosa
#12
Mette Marcussen, Julie Støve Bødker, Heidi Søgaard Christensen, Preben Johansen, Søren Nielsen, Ilse Christiansen, Olav Jonas Bergmann, Martin Bøgsted, Karen Dybkær, Mogens Vyberg, Hans Erik Johnsen
BACKGROUND: Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. METHODS AND FINDINGS: Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration...
2017: PloS One
https://www.readbyqxmd.com/read/28052008/targeting-p-glycoprotein-function-p53-and-energy-metabolism-combination-of-metformin-and-2-deoxyglucose-reverses-the-multidrug-resistance-of-mcf-7-dox-cells-to-doxorubicin
#13
Chaojun Xue, Changyuan Wang, Yaoting Sun, Qiang Meng, Zhihao Liu, Xiaokui Huo, Pengyuan Sun, Huijun Sun, Xiaodong Ma, Xiaochi Ma, Jinyong Peng, Kexin Liu
Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/Dox cells. Combination of the two drugs resumed p53 function via inhibiting overexpression of murine doubleminute 2(MDM2) and murine doubleminute 4(MDM4) leading to G2/M arrest and apoptosis in MCF-7/Dox cells...
December 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/28050764/polymorphisms-in-apoptosis-related-genes-in-cutaneous-melanoma-prognosis-sex-disparity
#14
Cristiane Oliveira, Gustavo Jacob Lourenço, José Augusto Rinck-Junior, Aparecida Machado de Moraes, Carmen Silvia Passos Lima
Cutaneous melanoma (CM) cells are resistant to apoptosis, and steroid hormones are involved in this process through regulation of TP53, MDM2, BAX, and BCL2 expression. We analyzed herein sex differences in outcomes of CM patients associated with TP53 c.215G>C, MDM2 c.309T>G, BAX c.-248G>A, and BCL2 c.-717C>A polymorphisms. DNA from 121 men and 116 women patients was analyzed by polymerase chain reaction and enzymatic digestion assays. At 60 months of follow-up, shorter progression-free survival (PFS) was seen in males with MDM2 GG + BCL2 AA (20...
February 2017: Medical Oncology
https://www.readbyqxmd.com/read/28050229/dual-function-of-mdm2-and-mdmx-toward-the-tumor-suppressors-p53-and-rb
#15
REVIEW
Jesús Hernández-Monge, Adriana Berenice Rousset-Roman, Ixaura Medina-Medina, Vanesa Olivares-Illana
The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX...
September 2016: Genes & Cancer
https://www.readbyqxmd.com/read/28049824/p53-pathway-is-involved-in-cell-competition-during-mouse-embryogenesis
#16
Guoxin Zhang, Yinyin Xie, Ying Zhou, Cong Xiang, Lai Chen, Chenxi Zhang, Xiaoshuang Hou, Jiong Chen, Hui Zong, Geng Liu
The function of tumor suppressor p53 has been under intense investigation. Acute stresses such as DNA damage are able to trigger a high level of p53 activity, leading to cell cycle arrest or apoptosis. In contrast, the cellular response of mild p53 activity induced by low-level stress in vivo remains largely unexplored. Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53. Here, we used the strategy of haploinsufficiency of Mdm2 and Mdm4 to induce mild p53 activation in vivo and found that Mdm2(+/-)Mdm4(+/-) double-heterozygous mice exhibited normal embryogenesis...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28048940/towards-understanding-the-molecular-recognition-of-albumin-by-p53-activating-stapled-peptide-atsp-7041
#17
Garima Tiwari, Chandra S Verma
Reactivation of tumor suppressing activity of p53 protein by targeting its negative regulator MDM2/MDMX has been pursued as a potential anticancer strategy. A promising dual inhibitor of MDM2/MDMX that has been developed and is currently in clinical trials is the stapled-peptide ATSP-7041. The activity of this molecule is reported to be modulated in the presence of serum. Albumin is the most abundant protein in serum and is known to bind reversibly to several molecules. To study this interaction, we develop a protocol combining molecular modeling, docking and simulations...
January 3, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28045062/modifying-effect-of-mouse-double-minute-2-promoter-variants-on-risk-of-recurrence-for-patients-with-squamous-cell-carcinoma-of-oropharynx
#18
Yang Zhang, Erich M Sturgis, Yuncheng Li, Qingyi Wei, Zhigang Huang, Guojun Li
Functional mouse double minute-2 (MDM2) promoter variants may alter MDM2 expression and thus affect radiotherapy response and prognosis of squamous cell carcinoma of oropharynx (SCCOP). Thus we assessed association of 2 functional MDM2 promoter variants with recurrence risk of SCCOP. The disease-free survival (DFS) of patients with MDM2rs2279744 TT or MDM2rs937283 AA genotypes was significantly reduced compared with that of patients with corresponding GT/GG or AG/GG genotypes. Multivariable analysis showed patients with TT or AA genotypes had a significantly higher risk of SCCOP recurrence than those with corresponding GT/GG or AG/GG genotypes did...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28042966/computed-binding-of-peptides-to-proteins-with-meld-accelerated-molecular-dynamics
#19
Joseph A Morrone, Alberto Perez, Justin L MacCallum, Ken A Dill
It has been a challenge to compute the binding poses and affinities of peptides to proteins by molecular dynamics (MD) simulation. Such computations would be valuable for capturing the physics and the conformational freedom of the molecules, but are currently too computationally expensive. Here we describe using MELD-accelerated MD for finding the binding poses and approximate relative binding free energies for flexible-peptide / protein interactions. MELD uses only weak information about the binding motif and not the detailed binding mode that is typically required by other free-energy-based methods...
January 2, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28042965/molecular-simulations-identify-binding-poses-and-approximate-affinities-of-stapled-%C3%AE-%C3%AF-%C3%AF-helical-peptides-to-mdm2-and-mdmx
#20
Joseph A Morrone, Alberto Perez, Qiaolin Deng, Sookhee Nicole Ha, M Katharine Holloway, Tom K Sawyer, Bradley S Sherborne, Frank K Brown, Ken A Dill
Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled helical peptides to the MDM2 and MDMX proteins. We employ free energy based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities...
January 2, 2017: Journal of Chemical Theory and Computation
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