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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/28077607/anatomy-of-mdm2-and-mdm4-in-evolution
#2
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/28069666/negative-auto-regulators-trap-p53-in-their-web
#3
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/28050229/dual-function-of-mdm2-and-mdmx-toward-the-tumor-suppressors-p53-and-rb
#4
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/28048940/towards-understanding-the-molecular-recognition-of-albumin-by-p53-activating-stapled-peptide-atsp-7041
#5
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
#6
Joseph A Morrone, Alberto Perez, Justin MacCallum, Ken A Dill
It has been a challenge to compute the poses and affinities for binding of peptides to proteins by molecular dynamics (MD) simulations. Such computations would be valuable for capturing the physics and the conformational freedom of the molecules, but they are currently too computationally expensive. Here we describe using MELD (Modeling Employing Limited Data)-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 19, 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-helical-peptides-to-mdm2-and-mdmx
#7
Joseph A Morrone, Alberto Perez, Qiaolin Deng, Sookhee N Ha, M Katharine Holloway, Tomi 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 α-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 19, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28035068/otub1-stabilizes-mdmx-and-promotes-its-proapoptotic-function-at-the-mitochondria
#8
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/27932484/role-of-mdm2-and-mdmx-in-dna-repair
#9
REVIEW
Christine M Eischen
Mdm2 and Mdmx are critical regulators of the p53 tumour suppressor and are overexpressed in many human malignancies. However, in recent years, their impact on genome instability was shown to be at least, in part, independent of p53. Both Mdm2 and Mdmx inhibit DNA break repair through their association with the Mre11/Rad50/Nbs1 DNA repair complex. Recent evidence indicates that harnessing Mdm2 and/or Mdmx-mediated inhibition of DNA break repair in cancer cells could provide a therapeutic opportunity, particularly for those malignancies that have lost functional p53...
December 8, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27927748/axl-receptor-signalling-suppresses-p53-in-melanoma-through-stabilization-of-the-mdmx-mdm2-complex
#10
Anna de Polo, Zhongling Luo, Casimiro Gerarduzzi, Xiang Chen, John B Little, Zhi-Min Yuan
Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27921263/overexpression-of-protein-phosphatase-1%C3%AE-pp1%C3%AE-is-associated-with-enhanced-cell-proliferation-and-poor-prognosis-in-hepatocellular-carcinoma
#11
Chunsun Li, Miaomiao Wu, Guijuan Zong, Chunhua Wan, Qingqing Liu, Huiling Zhou, Lu Hua, Yuyan Chen, Xudong Chen, Cuihua Lu
BACKGROUND: Protein phosphatase 1γ (PP1γ), as a member of the protein phosphatase 1 family, may be involved in regulation of multiple cellular processes, such as mitosis, cell survival, and apoptosis. However, little is known about the underlying mechanisms by which PP1γ regulates hepatocellular carcinoma development. AIM: We investigated the expression profile of PP1γ in hepatocellular carcinoma (HCC) cell lines and human HCC specimens, as well as its potential prognostic significance in HCC...
December 5, 2016: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/27904700/detection-of-gene-copy-number-alterations-in-dcis-and-invasive-breast-cancer-by-qm-fish
#12
Aifeng Pan, Yawei Zhou, Kun Mu, Yansong Liu, Feifei Sun, Peng Li, Li Li
The exact roles of copy number alteration (CNA) in initiation, progression and immunotherapy of breast cancer and the genomic alterations behind progression from ductal carcinoma in situ (DCIS) to invasive carcinoma remain unknown. Quantitative multi-gene fluorescence in situ hybridization (QM-FISH) opens a possibility of large scale genomic analysis of specific deletions and amplifications with high-resolution at one cell level. We detected CNAs of 30 genes using QM-FISH and analyzed their association with clinicopathological parameters and patients' outcomes in 66 breast cancers with synchronous invasive carcinoma and DCIS...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27820632/dna-duplex-based-photodynamic-molecular-beacon-for-targeted-killing-of-retinoblastoma-cell
#13
Yanchun Wei, Cuixia Lu, Qun Chen, Da Xing
Purposes: Retinoblastoma (RB) is the most common primary intraocular malignancy of infancy. An alternative RB treatment protocol is proposed and tested. It is based on a photodynamic therapy (PDT) with a designed molecular beacon that specifically targets the murine double minute x (MDMX) high-expressed RB cells. Methods: A MDMX mRNA triggered photodynamic molecular beacon is designed by binding a photosensitizer molecule (pyropheophorbide-a, or PPa) and a black hole quencher-3 (BHQ3) through a complementary oligonucleotide sequence...
November 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27780924/cddo-me-reveals-usp7-as-a-novel-target-in-ovarian-cancer-cells
#14
Dongjun Qin, Weiwei Wang, Hu Lei, Hao Luo, Haiyan Cai, Caixia Tang, Yunzhao Wu, Yingying Wang, Jin Jin, Weilie Xiao, Tongdan Wang, Chunmin Ma, Hanzhang Xu, Jinfu Zhang, Fenghou Gao, Ying-Li Wu
Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones...
November 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27777309/human-epidermal-growth-factor-receptor-4-her4-suppresses-p53-protein-via-targeting-the-mdmx-mdm2-protein-complex-implication-of-a-novel-mdmx-ser-314-phosphosite
#15
Casimiro Gerarduzzi, Anna de Polo, Xue-Song Liu, Manale El Kharbili, John B Little, Zhi-Min Yuan
Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27709883/a-unique-mdm2-binding-mode-of-the-3-pyrrolin-2-one-and-2-furanone-based-antagonists-of-the-p53-mdm2-interaction
#16
Ewa Surmiak, Aleksandra Twarda-Clapa, Krzysztof M Zak, Bogdan Musielak, Marcin D Tomala, Katarzyna Kubica, Przemyslaw Grudnik, Mariusz Madej, Mateusz Jablonski, Jan Potempa, Justyna Kalinowska-Tluscik, Alexander Dömling, Grzegorz Dubin, Tad A Holak
The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now...
December 16, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/27694836/the-zn-finger-domain-of-mdmx-suppresses-cancer-progression-by-promoting-genome-stability-in-p53-mutant-cells
#17
Z Matijasevic, A Krzywicka-Racka, G Sluder, J Gallant, S N Jones
The MDMX (MDM4) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by binding p53 tumor suppressor protein to inhibit p53-mediated transcription, and by complexing with MDM2 oncoprotein to promote MDM2-mediated degradation of p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of human tumors that are mutated for p53, often correlating with more aggressive cancers and a worse patient prognosis...
October 3, 2016: Oncogenesis
https://www.readbyqxmd.com/read/27432230/platycodin-d-a-metabolite-of-platycodin-grandiflorum-inhibits-highly-metastatic-mda-mb-231-breast-cancer-growth-in%C3%A2-vitro-and-in-vivo-by-targeting-the-mdm2-oncogene
#18
Ya Kong, Zong-Liang Lu, Jia-Jia Wang, Rui Zhou, Jing Guo, Jie Liu, Hai-Lan Sun, He Wang, Wei Song, Jian Yang, Hong-Xia Xu
The objective of the present study was to explore the in vitro and in vivo anticancer effects of Platycodin D (PD), derived from Platycodin grandiflorum, on highly metastatic MDA-MB-231 breast cancer cells. Using the MTT assay, we found that PD inhibited MDA-MB-231 cell growth in a concentration-dependent manner, with an IC50 value of 7.77±1.86 µM. Further studies showed that PD had anti-proliferative effects and induced cell cycle arrest in the G0/G1 phase. To explore the detailed mechanism(s) by which PD suppressed MDA-MB-231 cell growth, western blot analyses were used to detect the expression levels of proteins related to cell proliferation and survival...
September 2016: Oncology Reports
https://www.readbyqxmd.com/read/27375027/p53-binds-the-mdmx-mrna-and-controls-its-translation
#19
A-S Tournillon, I López, L Malbert-Colas, S Findakly, N Naski, V Olivares-Illana, K Karakostis, B Vojtesek, K Nylander, R Fåhraeus
MDMX and MDM2 are two nonredundant essential regulators of p53 tumor suppressor activity. MDM2 controls p53 expression levels, whereas MDMX is predominantly a negative regulator of p53 trans-activity. The feedback loops between MDM2 and p53 are well studied and involve both negative and positive regulation on transcriptional, translational and post-translational levels but little is known on the regulatory pathways between p53 and MDMX. Here we show that overexpression of p53 suppresses mdmx mRNA translation in vitro and in cell-based assays...
July 4, 2016: Oncogene
https://www.readbyqxmd.com/read/27373663/functional-interrogation-of-the-n-terminal-lid-of-mdmx-in-p53-binding-via-native-chemical-ligation
#20
Xishan Chen, Weiyue Lu
The homologous proteins MDM2 and MDMX negatively regulate the tumor suppressor protein p53 by antagonizing p53 transactivation activity and targeting p53 for degradation. MDM2 and MDMX bind to p53 via N-terminal p53-binding domains to control the level of p53. The N-terminal regions of MDM2 and MDMX are modified in vivo under stressed conditions, suggesting that modifications to MDM2/MDMX also may affect the p53-MDM2/MDMX interaction. Ample evidence suggests that the MDM2 lid (residues 1-24) is partially structured and significantly reduces its binding affinity with p53 several fold...
2016: Chemical & Pharmaceutical Bulletin
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