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https://www.readbyqxmd.com/read/28096294/mouse-modeling-of-the-mdm2-mdmx-p53-signaling-axis
#1
REVIEW
Nicole R Tackmann, Yanping Zhang
It is evident that p53 activity is critical for tumor prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and MDMX are thought to be critical for deciding the fate of p53, both through inhibitory binding and posttranslational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our interpretations of how p53 is regulated by MDM2 and MDMX...
January 17, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28096293/the-role-of-mdm2-and-mdm4-in-breast-cancer-development-and-prevention
#2
REVIEW
Sue Haupt, Reshma Vijayakumaran, Jeffreena Panimaya, Andrew Burgess, Elgene Lim, Ygal Haupt
The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defense against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery...
January 17, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28096292/regulation-of-kidney-development-by-the-mdm2-mdm4-p53-axis
#3
REVIEW
Samir El-Dahr, Sylvia Hilliard, Zubaida Saifudeen
While p53 activity is required for tumor suppression, unconstrained p53 activity on the other hand is detrimental to the organism, resulting in inappropriate cellular death or proliferation defects. Unimpeded p53 activity is lethal in the developing embryo, underlining the need for maintaining a tight control on p53 activity during this period. The critical role of the negative regulators of p53, Mdm2 and Mdm4, in vertebrate development came to light by fatal disruption of embryogenesis that was observed with Mdm2 and Mdm4 gene deletions in mice...
January 17, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28093454/mdm-proteins-critical-regulators-of-embry-ogenesis-and-homeostasis
#4
REVIEW
Sydney M Moyer, Connie A Larsson, Guillermina Lozano
Mdm2 and Mdm4 are negative regulators of the tumor suppressor p53; hence, this relationship is the focus of many cancer related studies. A multitude of experiments across various developmental stages have been conducted to explore the tissue-specific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germline or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethality. Mdm2 loss is often more deleterious than loss of its homolog Mdm4 All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes...
January 15, 2017: Journal of Molecular Cell Biology
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
#5
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/28077607/anatomy-of-mdm2-and-mdm4-in-evolution
#6
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/28071670/benzyl-isothiocyanate-potentiates-p53-signaling-and-antitumor-effects-against-breast-cancer-through-activation-of-p53-lkb1-and-p73-lkb1-axes
#7
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
#8
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
#9
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
#10
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/28063307/sharpin-facilitates-p53-degradation-in-breast-cancer-cells
#11
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/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/28050229/dual-function-of-mdm2-and-mdmx-toward-the-tumor-suppressors-p53-and-rb
#14
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
#15
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 17, 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
#16
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/28042966/computed-binding-of-peptides-to-proteins-with-meld-accelerated-molecular-dynamics
#17
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/28035068/otub1-stabilizes-mdmx-and-promotes-its-proapoptotic-function-at-the-mitochondria
#18
Yingxiao Chen, Yue-Gang Wang, Yuhuang Li, Xiao-Xin Sun, Mu-Shui Dai
Otub1 regulates p53 stability and activity via non-canonical inhibition of UbcH5, the MDM2 cognate ubiquitin-conjugating enzyme (E2). However, whether Otub1 regulates MDMX stability and activity is not clear. Here we report that Otub1 also suppresses MDM2-mediated MDMX ubiquitination in cells and in vitro, independently of its deubiquitinating enzyme activity. Consequently, overexpression of Otub1 markedly stabilized MDMX and increased its levels, whereas knockdown of Otub1 reduced the levels of MDMX. Interestingly, MDMX induced by Otub1 can localize to mitochondria in addition to the cytosol, enhance p53 phosphorylation at S46 (p53S46P) and promote mitochondria-mediated apoptotic pathway...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/28032591/the-pre-existing-population-of-5s-rrna-effects-p53-stabilization-during-ribosome-biogenesis-inhibition
#19
Carmine Onofrillo, Alice Galbiati, Lorenzo Montanaro, Massimo Derenzini
Pre-ribosomal complex RPL5/RPL11/5S rRNA (5S RNP) is considered the central MDM2 inhibitory complex that control p53 stabilization during ribosome biogenesis inhibition. Despite its role is well defined, the dynamic of 5S RNP assembly still requires further characterization. In the present work, we report that MDM2 inhibition is dependent by a pre-existing population of 5S rRNA.
December 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/28031409/functional-activation-of-mutant-p53-by-platinum-analogs-in-cisplatin-resistant-cells-is-dependent-on-phosphorylation
#20
Xiaolei Xie, Guangan He, Zahid H Siddik
: Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently we reported that mutant, but otherwise functional, p53V172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogs oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP), strongly stabilize and activate p53V172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2...
December 28, 2016: Molecular Cancer Research: MCR
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