Xiyao Cheng, Rong Chen, Ting Zhou, Bailing Zhang, Zichun Li, Meng Gao, Yongqi Huang, Huili Liu, Zhengding Su,
Abstract Overexpressed Mdm2 and its 7homolog MdmX impair p53 activity in many cancers. Small molecules mimicking a p53 peptide can effectively inhibit Mdm2 but not MdmX. Here, we show a strategy for improving lead compounds for Mdm2 and MdmX inhibition based on the multivalency of the p53 peptide. Crystal structures of MdmX complexed with nutlin-3a, a strong Mdm2 inhibitor but a weak one for MdmX, reveal that nutlin-3a fits into the ligand binding pocket of MdmX mimicking the p53 peptide. However, due to distinct ...
Tópico(s): HIV Research and Treatment
2022 - Nature Portfolio | Nature Communications
Koki Ueda, Rajni Kumari, Emily Schwenger, Justin C. Wheat, Oliver Bohorquez, Swathi-Rao Narayanagari, Samuel J. Taylor, Luis A. Carvajal, Kith Pradhan, Boris Bartholdy, Tihomira I. Todorova, Hiroki Goto, Daqian Sun, Jiahao Chen, Jidong Shan, Yinghui Song, Cristina Montagna, Shunbin Xiong, Guillermina Lozano, Andrea Pellagatti, Jacqueline Boultwood, Amit Verma, Ulrich Steidl,
MDMX is overexpressed in the vast majority of patients with acute myeloid leukemia (AML). We report that MDMX overexpression increases preleukemic stem cell (pre-LSC) number ... five newly generated murine models, we found that MDMX overexpression triggers progression of multiple chronic/asymptomatic preleukemic ... overt AML. Transcriptomic and proteomic studies revealed that MDMX overexpression exerts this function, unexpectedly, through activation of Wnt/β-Catenin signaling in pre-LSCs. Mechanistically, MDMX binds CK1α and leads to accumulation of β- ...
Tópico(s): Protein Degradation and Inhibitors
2021 - Cell Press | Cancer Cell
Xiang Li, Neelakshi Gohain, Si Chen, Yinghua Li, Xiaoyuan Zhao, Bo Li, William D. Tolbert, Wangxiao He, Marzena Pazgier, Honggang Hu, Wuyuan Lu,
... protein P53 with its negative regulators MDM2 and MDMX activates P53 in vitro and in vivo, representing ... TSFAEYWNLLSP), with binding affinities for both MDM2 and MDMX in the low nanomolar concentration range. Here we ... affinity, dual-specificity peptide antagonist of MDM2 and MDMX obtained through systematic mutational analysis and additivity-based ... PMI-M3 (LTFLEYWAQLMQ) that bound to MDM2 and MDMX with Kd values in the low picomolar concentration ... calorimetry. Co-crystal structures of MDM2 and of MDMX in complex with PMI-M3 were solved at ...
Tópico(s): Bacteriophages and microbial interactions
2021 - Elsevier BV | Acta Pharmaceutica Sinica B
Herui Wang, Bin Li, Kulsum Asha, Ryan L. Pangilinan, Asha Thuraisamy, Harman Chopra, Susumu Rokudai, Yong Yu, Carol Prives, Yan Zhu,
... has been linked to human diseases, including cancer. MDMX, a crucial zinc-containing negative regulator of p53, ... ion chelator TPEN or Chelex resin results in MDMX protein degradation in a ubiquitination-independent and 20S ... zinc led to recovery of cellular levels of MDMX. Further, TPEN treatment inhibits growth of the MCF- ... line, which is partially rescued by overexpression of MDMX. Moreover, in a mass-spectrometry-based proteomics analysis, ... a zinc-permeable ion channel, as a novel MDMX-interacting protein. TRPM7 stabilizes and induces the appearance ...
Tópico(s): Magnesium in Health and Disease
2021 - Elsevier BV | Journal of Biological Chemistry
Olga Egorova, Heather HC Lau, Kate McGraphery, Yi Sheng,
... p53 occurs in most human cancers. Mdm2 and MdmX are homologous proteins from the Mdm (Murine Double ... the ubiquitin proteolytic system and by Mdm2 and MdmX mediated inhibition of p53 transactivation. To investigate the role of the RING domain of Mdm2 and MdmX, an analysis of the distinct functionalities of individual ... in the cell nucleus, contrasting the localization of MdmX RING domain in the cytoplasm. Mdm2 RING was ... to possess an endogenous E3 ligase activity, whereas MdmX RING did not. Both Mdm2 and MdmX RING ...
Tópico(s): Epigenetics and DNA Methylation
2020 - Multidisciplinary Digital Publishing Institute | International Journal of Molecular Sciences
Divya Venkatesh, Nicholas A. O'Brien, Fereshteh Zandkarimi, David Tong, Michael E. Stokes, Denise Dunn, Everett S. Kengmana, Allegra T. Aron, Alyssa M. Klein, J. Csuka, Sung‐Hwan Moon, Marcus Conrad, Christopher J. Chang, Donald C. Lo, Angelo D’Alessandro, Carol Prives, Brent R. Stockwell,
MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53' ... less information available about p53-independent roles of MDMX or the MDM2–MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. ... molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ...
Tópico(s): RNA modifications and cancer
2020 - Cold Spring Harbor Laboratory Press | Genes & Development
Chong Gao, Gu Xiao, Alessandra Piersigilli, Jiangtao Gou, Olorunseun O. Ogunwobi, Jill Bargonetti,
... the E3 ubiquitin ligase MDM2 and its homolog MDMX. Expression of MDM2 and MDMX occurs in estrogen receptor α-positive (ERα+) breast ... There are p53-independent influences of MDM2 and MDMX, and 80% of TNBC express mutant p53 (mtp53). ... but the context-dependent influences of MDM2 and MDMX on different subtypes of breast cancers expressing mtp53 ... context-dependent roles, we carried out MDM2 and MDMX knockdown in orthotopic tumors of TNBC MDA-MB- ... qRT-PCR and Western blot analysis. Knocking down MDMX or MDM2 in MDA-MB-231 cells reduced ...
Tópico(s): Cancer Cells and Metastasis
2019 - BioMed Central | Breast Cancer Research
Pavlína Kosztyu, Iva Slaninová, Barbora Valčíková, Amandine Verlande, Petr Müller, Jan Paleček, Stjepan Uldrijan,
Mdm2 and MdmX are related proteins serving in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer as an E3 ubiquitin ligase for the ... exchanging parts of the RING with the corresponding MdmX sequence, to identify the molecular determinants of this difference. Mdm2 can also promote MdmX degradation, and we identified several mutations blocking it. ... Mdm2/E2 interface and did not disrupt the MdmX-Mdm2 interaction. Surprisingly, some mutations of the Mdm2/E2 interface inhibited MdmX degradation, which is mediated by the Mdm2/MdmX ...
Tópico(s): Epigenetics and DNA Methylation
2019 - Frontiers Media | Frontiers in Physiology
Mengxin Li, Yalong Cong, Yuchen Li, Susu Zhong, Ran Wang, Hao Li, Lili Duan,
The study of the p53-MDMX/MDM2 binding sites is a research hotspot for tumor drug design. The inhibition of p53-targeted MDMX/MDM2 has become an effective approach in anti- ... the difference in the binding mechanism between p53-MDMX and p53-MDM2. The interaction of a 12mer ... which is similar to p53 in structure, with MDMX/MDM2 is also studied. The results demonstrate that ... with MDM2 generates a stronger interaction than with MDMX. Compared to p53, pDIQ has larger binding free energies with MDMX and MDM2. According to the calculated binding free ...
Tópico(s): DNA and Nucleic Acid Chemistry
2019 - Frontiers Media | Frontiers in Chemistry
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 ... 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. Consistent ...
Tópico(s): Cell death mechanisms and regulation
2018 - American Association for Cancer Research | Cancer Research
Dading Huang, Yifei Qi, Jianing Song, John Z. H. Zhang,
... hot and warm spots in p53/PMI‐MDM2/MDMX protein–protein interaction systems. Comparison of the calculated ... P53 and PMI proteins interacting with MDM2 and MDMX shows a good quantitative agreement with the available ... our calculation predicted hot spots in MDM2 and MDMX proteins in their interactions with P53 and PMI ... and warm spots and binds stronger to MDM2/MDMX. The analysis of these hot and warm spots ... binding between P53 and PMI to the MDM2/MDMX systems. Specifically, for p53/PMI‐MDM2 systems, p53 ...
Tópico(s): Enzyme Structure and Function
2018 - Wiley | Journal of Computational Chemistry
Ning Kon, Donglai Wang, Tongyuan Li, Le Jiang, Li Qiang, Wei Gu,
... author Correspondence to: Wei Gu, email: // Keywords : p53; Mdmx; Mdm4; metabolism; adipose tissues Received : September 26, 2017 ... activities has an independent role beyond tumor suppression. Mdmx (also called Mdm4), like Mdm2, acts as a ... suppressor of p53 but the embryonic lethality of mdmx-null mice creates difficulties to evaluate its physiological ... the embryonic lethality caused by the deficiency of mdmx , in contrast to the case for mdm2 , is ... cycle arrest, senescence and apoptosis. p53 3KR/3KR /mdmx -/- mice are healthy but skinny without obvious developmental ...
Tópico(s): Metabolism, Diabetes, and Cancer
2018 - Impact Journals LLC | Oncotarget
Georgios Valianatos, Barbora Valčíková, Kateřina Growková, Amandine Verlande, Jitka Mlčochová, Lenka Radová, Monika Štětková, Michaela Vyhnakova, Ondřej Slabý, 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, ... identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, ... interfering with cellular splicing machinery can result in MdmX downregulation in cancer cells. We, therefore, hypothesized that ... splicing machinery, activate p53 in melanoma cells overexpressing MdmX. We found that enoxacin and ciprofloxacin, a related ...
Tópico(s): RNA Interference and Gene Delivery
2017 - Public Library of Science | PLoS ONE
Anna de Polo, Zhongling Luo, Casimiro Gerarduzzi, Xiang Chen, John B. Little, Zhi-Min Yuan,
... tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in ... growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity. Upon activation, AXL stabilizes MDMX through a post-translational modification that involves phosphorylation of MDMX on the phosphosite Ser314, leading to increased affinity between MDMX and MDM2 and favouring MDMX nuclear translocation. Ser314 phosphorylation can also protect MDMX from MDM2-mediated degradation, leading to stabilization of ...
Tópico(s): Cancer Mechanisms and Therapy
2016 - Oxford University Press | Journal of Molecular Cell Biology
Jesús Hernández‐Monge, Adriana Berenice Rousset-Roman, Ixaura Medina‐Medina, Vanesa Olivares‐Illana,
... most types of human cancer.The proto-oncoproteins MDMX and MDM2 are the main regulators of the ... suppressor p53 protein.Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional ... activity, for which MDM2 needs to dimerize with MDMX.Under genotoxic stress conditions, both become positive regulators ... p53.The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation.MDM2 and MDMX are also being revealed as effective regulators of ...
Tópico(s): Ubiquitin and proteasome pathways
2016 - SAGE Publishing | Genes & Cancer
Yingxiao Chen, Yue-Gang Wang, Yuhuang Li, Xiao‐Xin Sun, Mu‐Shui Dai,
... Dai, email: daim@ohsu.edu Keywords: deubiquitinating enzymes, MDMX, Otub1, p53, apoptosis Received: November 04, 2016 Accepted: ... 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 ... 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 ...
Tópico(s): DNA Repair Mechanisms
2016 - Impact Journals LLC | Oncotarget
Christy R. Grace, David Ban, Jaeki Min, Anand Mayasundari, Lie Min, Kristin E. Finch, Lyra Griffiths, Nagakumar Bharatham, Donald Bashford, R. Kiplin Guy, Michael A. Dyer, Richard W. Kriwacki,
... overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, ... can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series ... Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) ... structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with ... of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX ...
Tópico(s): Protein Structure and Dynamics
2016 - Elsevier BV | Journal of Molecular Biology
Zdenka Matijašević, Anna Krzywicka-Racka, Greenfield Sluder, Jean‐Nicolas Gallant, Stephen N. Jones,
Abstract The MDMX ( MDM4 ) oncogene is amplified or overexpressed in a significant percentage of human tumors. MDMX is thought to function as an oncoprotein by ... p53. However, down-regulation or loss of functional MDMX has also been observed in a variety of ... We have previously reported that endogenous levels of MdmX can suppress proliferation and promote pseudo-bipolar mitosis ... cells derived from p53-deficient mice, and that MdmX-p53 double deficient mice succumb to spontaneously formed ... p53-deficient mice. These results suggest that the MdmX oncoprotein may act as a tumor-suppressor in ...
Tópico(s): RNA Research and Splicing
2016 - Springer Nature | Oncogenesis
Lihong Chen, Wade M. Borcherds, Shaofang Wu, Andreas Becker, E. Schönbrunn, Gary W. Daughdrill, Jiandong Chen,
Significance MDMX protein is a critical regulator of p53 and a novel drug target. The current generation of MDM2 inhibitors does not inhibit MDMX. Therefore, their therapeutic efficacy will be influenced by poorly characterized MDMX functional status in tumors. Efforts to develop MDMX inhibitors have been largely unsuccessful, indicating gaps in our understanding of the structure and regulation of MDMX. This study provides evidence that MDMX-p53 binding is regulated by an autoinhibitory mechanism ...
Tópico(s): Ubiquitin and proteasome pathways
2015 - National Academy of Sciences | Proceedings of the National Academy of Sciences
Jianzhong Chen, Jinan Wang, Qinggang Zhang, Kaixian Chen, Weiliang Zhu,
Abstract Binding abilities of current inhibitors to MDMX are weaker than to MDM2. Polarizable molecular dynamics simulations (MD) followed by Quantum mechanics/molecular mechanics generalized Born surface area (QM//MM-GBSA) ... the binding difference of inhibitors to MDM2 and MDMX. The predicted binding free energies not only agree ... in van der Walls interactions of inhibitors with MDMX relative to MDM2 is a main factor of weaker bindings of inhibitors to MDMX. The analyses of dihedral angles based on MD ...
Tópico(s): Enzyme Structure and Function
2015 - Nature Portfolio | Scientific Reports
Sue Haupt, D Buckley, J-MB Pang, J Panimaya, Piotr J. Paul, Cristina Gamell, Elena A. Takano, Y Ying Lee, Sanne Hiddingh, T-M Rogers, Amina F.A.S. Teunisse, Marco J. Herold, Jean‐Christophe Marine, Stephen B. Fox, Aart G. Jochemsen, Ygal Haupt,
... of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), ... wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial ... with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the ... in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition ... a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth ...
Tópico(s): Cancer Research and Treatments
2015 - Springer Nature | Cell Death and Disease
X Chen, Neelakshi Gohain, Changyou Zhan, W-Y Lu, Marzena Pazgier, Wuyuan Lu,
... the E3 ubiquitin ligase MDM2 and its homolog MDMX. Under stressed conditions such as DNA damage, p53 escapes MDM2- and MDMX-mediated functional inhibition and degradation, acting to prevent ... that stress signals induce phosphorylation of MDM2 and MDMX, leading to p53 activation. However, the structural basis ... means to produce site-specifically phosphorylated MDM2 and MDMX proteins for biochemical and biophysical studies. Herein, we ... chemical ligation, and functional characterization of (24–108)MDMX and its Tyr99-phosphorylated analog with respect to ...
Tópico(s): Cancer Research and Treatments
2015 - Springer Nature | Oncogene
Wenjie Wu, Chao Xu, Xing Ling, Chuandong Fan, Brian Buckley, Mikhail V. Chernov, Leigh Ellis, F Li, Inés G. Muñoz, X Wang,
... WT) p53 . Targeting the Mdm2–p53 interface or MdmX ((MDM4), mouse double minute 4)–p53 interface or ... However, targeting the E3 ligase activity of Mdm2–MdmX really interesting new gene (RING)–RING interaction as ... and characterization of small molecule inhibitors targeting Mdm2–MdmX RING–RING interaction as a new class of ... library, we identified inhibitors (designated as MMRis (Mdm2–MdmX RING domain inhibitors)) that specifically inhibit Mdm2–MdmX E3 ligase activity toward Mdm2 and p53 substrates. ... its analog MMRi64 are capable of disrupting Mdm2–MdmX interactions in vitro and activating p53 in cells. ...
Tópico(s): Microtubule and mitosis dynamics
2015 - Springer Nature | Cell Death and Disease
Patrick L. Leslie, Hengming Ke, Yanping Zhang,
... with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through ... RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. ... intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an ... of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2-MDMX heterodimerization requires the extreme C terminus and proper ... with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through ...
Tópico(s): Microtubule and mitosis dynamics
2015 - Elsevier BV | Journal of Biological Chemistry
Alexia M. Carrillo, Alyssa Bouska, Maria P. Arrate, Christine M. Eischen,
The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but ... 90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced ... breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as ...
Tópico(s): Epigenetics and DNA Methylation
2014 - Springer Nature | Oncogene
Mdm2 and MdmX are important negative regulators of the tumor suppressor p53. Structurally homologous Mdm2 and MdmX inhibit p53 by directly blocking p53 transcriptional activation. ... mediated by its C-terminal RING domain. However, MdmX lacks intrinsic E3 ligase activity and fails to ... a comparative structural analysis between the Mdm2 and MdmX RING domains offers a unique way to elucidate ... ubiquitination. We performed site-directed mutagenesis of the MdmX RING domain and found that the substitution of ...
Tópico(s): Microtubule and mitosis dynamics
2014 - Elsevier BV | Biochemical and Biophysical Research Communications
Aishwarya G. Jacob, Ravi K. Singh, Daniel F. Comiskey, Matthew F. Rouhier, Fuad Mohammad, Thomas W. Bebee, Dawn S. Chandler,
MDM2 and MDMX are the chief negative regulators of the tumor-suppressor protein p53 and are essential for maintaining homeostasis within ... and also in several cancer types, MDM2 and MDMX are alternatively spliced. The splice variants MDM2-ALT1 and MDMX-ALT2 lack the p53-binding domain and are ... pathway and the nature of its interaction with MDMX remain unclear. Also, the role of the architecturally similar MDMX-ALT2 and its influence of the MDM2-MDMX-p53 axis are yet to be elucidated. We ... MDM2-ALT1 is capable of binding full-length MDMX as well as full-length MDM2. Additionally, we ...
Tópico(s): Microtubule and mitosis dynamics
2014 - Public Library of Science | PLoS ONE
Xiang Ling, Chao Xu, Chuandong Fan, Kai Zhong, Fengzhi Li, Xinjiang Wang,
... MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a ... FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2–MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2–p53 interactions and moderately increases Mdm2–MdmX interactions, suggesting a change of targeting specificity of Mdm2–MdmX E3 complex from p53 to MdmX, resulting in ...
Tópico(s): Ubiquitin and proteasome pathways
2014 - American Association for Cancer Research | Cancer Research
Qiong Yu, Yan Li, Kun Mu, Zhishuang Li, Qingyong Meng, Xiaojuan Wu, Yan Wang, Li Li,
... cancers. The murine double minute 2 (Mdm2) and Mdmx represent two important cellular regulators of p53. The ... study was to evaluate the abnormalities of p53, Mdmx and Mdm2 genes in archived breast cancers. We assessed the genetic instability at p53, Mdmx and Mdm2 using high resolution multi-color fluorescent ... expression status of the tumor protein p53 (TP53), MDMx and MDM2 by immunohistochemistry in 115 archived samples ... high grade, ER negative and high ki67 tumors. Mdmx amplification with low-level increase of gene copy ...
Tópico(s): RNA modifications and cancer
2014 - BioMed Central | Diagnostic Pathology
Daniel J. Colacurcio, Alyssa Yeager, Dennis L. Kolson, Kelly L. Jordan‐Sciutto, Cagla Akay,
... vitro. In addition, we have previously shown that MDMx (also referred to as MDM4), a negative regulator ... HIV-induced CNS neurodegeneration. Thus, we hypothesized that MDMx provides indirect neuroprotection from HIV-induced neurodegeneration in ... In this report, we found significant reductions in MDMx protein levels in the mid-frontal cortex of ... to NMDA receptor- and calpain-dependent degradation of MDMx and decreased neuronal survival, while overexpression of MDMx conferred partial protection from HIV M/M toxicity ...
Tópico(s): RNA Interference and Gene Delivery
2013 - Elsevier BV | Molecular and Cellular Neuroscience