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Zhaodi Zheng, Wenzhen Zhu, Bingwu Yang, Rongfei Chai, Tingting Liu, Fenglin Li, Guanghui Ren, Shuhua Ji, Shan Liu, Guorong Li
Metformin, a widely used antidiabetic drug, exhibits anticancer effects which are mediated by the phosphatidylinositol 3-kinase (PI3K)/serine/threonine kinase (AKT) signaling pathway. However, its use in anticancer therapy combined with other natural products remains unclear. Flavone as the core structure of flavonoids has been demonstrated to induce cell apoptosis without causing serious side effect. Murine double minute X (MDMX) inhibits tumor suppressor gene p53 whose function is associated with the PI3K/AKT pathway...
April 2018: Oncology Letters
Gamze Kuser-Abali, Lu Gong, Jiawei Yan, Qingqing Liu, Weiqi Zeng, Amanda Williamson, Chuan Bian Lim, Mary Ellen Molloy, John B Little, Lei Huang, Zhi-Min Yuan
Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation...
March 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dawei Li, Omid Tavana, Shao-Cong Sun, Wei Gu
Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx in vitro and in vivo and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx which in turn resulted in p53 activation...
March 9, 2018: Cancer Research
Ning Kon, Donglai Wang, Tongyuan Li, Le Jiang, Li Qiang, Wei Gu
Although cell-cycle arrest, senescence and apoptosis remain as major canonical activities of p53 in tumor suppression, the emerging role of p53 in metabolism has been a topic of great interest. Nevertheless, it is not completely understood how p53-mediated metabolic activities are regulated in vivo and whether this part of the activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a major suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological significance in metabolism...
January 26, 2018: Oncotarget
Harman Chopra, Zara Khan, Jamie Contreras, Herui Wang, Abanob Sedrak, Yan Zhu
Castration-resistant prostate cancer (CRPC) frequently develops after initial standard radiation and androgen deprivation therapy, leaving patients with limited further treatment options. Androgen receptor (AR) is a transcription factor that plays a key role in the initiation and progression of prostate cancer. p53, a major tumor suppressor that is rarely mutated in early-stages of prostate cancer, is often deregulated during prostate cancer progression. Here, we report an unusual co-amplification of MDM2 and MDMX, two crucial negative regulators of p53, in CRPC datasets...
January 19, 2018: Oncotarget
Jane Vin Chan, Dawn Xin Ping Koh, Yun Liu, Thomas L Joseph, David P Lane, Chandra S Verma, Yaw Sing Tan
Murine double minute 4 protein (MDMX) is crucial for the regulation of the tumor suppressor protein p53. Phosphorylation of the N-terminal domain of MDMX is thought to affect its binding with the transactivation domain of p53, thus playing a role in p53 regulation. In this study, the effects of MDMX phosphorylation on the binding of p53 were investigated using molecular dynamics simulations. It is shown that in addition to the previously proposed mechanism in which phosphorylated Y99 of MDMX inhibits p53 binding through steric clash with P27 of p53, the N-terminal lid of MDMX also appears to play an important role in regulating the phosphorylation-dependent interactions between MDMX and p53...
December 22, 2017: Oncotarget
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
Hui Tian, Nicole R Tackmann, Aiwen Jin, Junnian Zheng, Yanping Zhang
The MDM2 RING domain harbors E3 ubiquitin ligase activity critical for regulating the degradation of tumor suppressor p53, which controls many cellular pathways. The MDM2 RING domain also is required for an interaction with MDMX. Mice containing a substitution in the MDM2 RING domain, MDM2C462A, disrupting MDM2 E3 function and the MDMX interaction, die during early embryogenesis that can be rescued by p53 deletion. To investigate whether MDM2C462A, which retains p53 binding, has p53-suppressing activity, we generated Mdm2C462A/C462A;p53ER/- mice, in which we replaced the endogenous p53 alleles with an inducible p53ER/- allele, and compared survival with that of similarly generated Mdm2-/-;p53ER/- mice...
November 9, 2017: Journal of Biological Chemistry
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally...
November 7, 2017: Biochemistry
Georgios Valianatos, Barbora Valcikova, Katerina Growkova, Amandine Verlande, Jitka Mlcochova, Lenka Radova, Monika Stetkova, Michaela Vyhnakova, Ondrej Slaby, Stjepan Uldrijan
MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation...
2017: PloS One
Olaf Merkel, Ninon Taylor, Nicole Prutsch, Philipp B Staber, Richard Moriggl, Suzanne D Turner, Lukas Kenner
The p53 tumor suppressor is inactivated in most cancers, thus suggesting that loss of p53 is a prerequisite for tumor growth. Therefore, its reintroduction through different means bears great clinical potential. After a brief introduction to current knowledge of p53 and its regulation by the ubiquitin-ligases MDM2/MDMX and post-translational modifications, we will discuss small molecules that are able to reactivate specific, frequently observed mutant forms of p53 and their applicability for clinical purposes...
July 2017: Mutation Research
Xiang Li, Chao Liu, Si Chen, Honggang Hu, Jiacan Su, Yan Zou
According to the previously reported potent dual l-peptide PMI of p53-MDM2/MDMX interactions, a series of d-amino acid mutational PMI analogues, PMI-1-4, with enhanced proteolytic resistence and in vitro tumor cell inhibitory activities were reported, of which Liposome-PMI-1 showed a stronger inhibitory activity against the U87 cell lines than Nutlin-3. This d-amino acid mutation strategy may give a hand for enhancing the potential of peptide drugs.
October 15, 2017: Bioorganic & Medicinal Chemistry Letters
Veronica Tisato, Rebecca Voltan, Arianna Gonelli, Paola Secchiero, Giorgio Zauli
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed...
July 3, 2017: Journal of Hematology & Oncology
Rong Chen, Jingjing Zhou, Lingyun Qin, Yao Chen, Yongqi Huang, Huili Liu, Zhengding Su
In nearly half of cancers, the anticancer activity of p53 protein is often impaired by the overexpressed oncoprotein Mdm2 and its homologue, MdmX, demanding efficient therapeutics to disrupt the aberrant p53-MdmX/Mdm2 interactions to restore the p53 activity. While many potent Mdm2-specific inhibitors have already undergone clinical investigations, searching for MdmX-specific inhibitors has become very attractive, requiring a more efficient screening strategy for evaluating potential scaffolds or leads. In this work, considering that the intrinsic fluorescence residue Trp23 in the p53 transaction domain (p53p) plays an important role in determining the p53-MdmX/Mdm2 interactions, we constructed a fusion protein to utilize this intrinsic fluorescence signal to monitor high-throughput screening of a compound library...
June 27, 2017: Biochemistry
Han Zhao, Yu-Zhuo Xie, Rui Xing, Ming Sun, Feng Chi, Yue-Can Zeng
PURPOSE: Chemoradiotherapy is the standard treatment modality for advanced non-small cell lung cancer (NSCLC). However, drug and radiation resistance remain major factors influencing its clinical outcome. The purpose of this study was to evaluate whether MDMX can affect the chemosensitivity and clinical outcome of NSCLC. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to assess MDMX mRNA expression levels in 105 primary NSCLC tissues, its corresponding non-cancerous tissues and two NSCLC-derived cell lines (A549 and SK-MES-1)...
August 2017: Cellular Oncology (Dordrecht)
Koji Nomura, Marta Klejnot, Dominika Kowalczyk, Andreas K Hock, Gary J Sibbet, Karen H Vousden, Danny T Huang
MDM2-MDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2-MDMX-E2(UbcH5B)-ubiquitin complex, we designed MDM2 mutants that prevent E2-ubiquitin binding without altering the RING-domain structure...
July 2017: Nature Structural & Molecular Biology
Wade Borcherds, Andreas Becker, Lihong Chen, Jiandong Chen, Lucía B Chemes, Gary W Daughdrill
MdmX contains an intramolecular binding motif that mimics the binding of the p53 tumor suppressor. This intramolecular binding motif is connected to the p53 binding domain of MdmX by a conserved flexible linker that is 85 residues long. The sequence of this flexible linker has an identity of 51% based on multiple protein sequence alignments of 52 MdmX homologs. We used polymer statistics to estimate a global KD value for p53 binding to MdmX in the presence of the flexible linker and the intramolecular binding motif by assuming the flexible linker behaves as a wormlike chain...
May 23, 2017: Biophysical Journal
Aleksandra Twarda-Clapa, Sylwia Krzanik, Katarzyna Kubica, Katarzyna Guzik, Beata Labuzek, Constantinos G Neochoritis, Kareem Khoury, Kaja Kowalska, Miroslawa Czub, Grzegorz Dubin, Alexander Dömling, Lukasz Skalniak, Tad A Holak
The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers...
May 25, 2017: Journal of Medicinal Chemistry
Lin Wang, Xiao-Cong Pang, Zi-Ru Yu, Sheng-Qian Yang, Ai-Lin Liu, Jin-Hua Wang, Guan-Hua Du
The aim of this study is to investigate the synergism of low dose of actinomycin D (LDActD) to the cytotoxicity of cisplatin (CDDP) on KB cells. The role of P53 reactivation by LDActD in the synergism and its mechanism were further studied. Cell viability was determined by MTT assay. Apoptosis was determined by AnnexinV-FITC/PI staining. Mitochondrial membrane potential (MMP) was detected by JC-1 staining. Expression of proteins was detected by Western blotting (WB) and/or immunofluorescence (IF). Molecular docking of actinomycin D (ACTD) to Mouse double minute 2 homolog (MDM2) and Mouse double minute 2 homolog X (MDMX)...
June 2017: Journal of Asian Natural Products Research
Xiong An Lee, Chandra Verma, Adelene Y L Sim
Mdm2 and MdmX share high structural similarity in their N-terminal domains, yet dual inhibitors are challenging to design due to differences in the conformations of the binding pockets, and notably of the proposed gatekeeper residue, Y100/99. Analysis of crystal structures and molecular dynamics (MD) simulations of complexes of Mdm2 and MdmX resulted in the identification of a water molecule with a long residence time that appears to be modulated by the conformation of Y100/99. These observations lead us to speculate that dual inhibitors either (i) stabilize both Mdm2 and MdmX with Y100/99 in the open conformation typically seen in complexes of Mdm2 with p53, or (ii) the dual inhibitors are agnostic to the conformation of Y100/99...
August 2017: Proteins
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