MDMX in Cancer: A Partner of p53 and a p53-Independent Effector

References

• Wade M, Li Y-C, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13(2):83–96. doi:10.1038/nrc3430
   PubMed Web of Science ®Google Scholar
• Feki A, Irminger-Finger I. Mutational spectrum of p53 mutations in primary breast and ovarian tumors. Crit Rev Oncol Hematol. 2004;52(2):103–116. doi:10.1016/j.critrevonc.2004.07.002
   PubMed Web of Science ®Google Scholar
• Oliner JD, Saiki AY, Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb Perspect Med. 2016;6(6):a026336. doi:10.1101/cshperspect.a026336
   PubMed Web of Science ®Google Scholar
• Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7):1126–1132. doi:10.1101/gad.7.7a.1126
   PubMedGoogle Scholar
• Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein. Cell Mol Life Sci. 1999;55(1):96–107. doi:10.1007/s000180050273
   PubMed Web of Science ®Google Scholar
• Shvarts A, Steegenga WT, Riteco N, et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996;15(19):5349–5357. doi:10.1002/j.1460-2075.1996.tb00919.x
   PubMed Web of Science ®Google Scholar
• Wang W, Qin -J-J, Rajaei M, et al. Targeting MDM2 for novel molecular therapy: beyond oncology. Med Res Rev. 2020;40(3):856–880. doi:10.1002/med.21637
   PubMed Web of Science ®Google Scholar
• Finch RA, Donoviel DB, Potter D, et al. mdmx is a negative regulator of p53 activity in vivo. Cancer Res. 2002;62(11):3221–3225.
   PubMed Web of Science ®Google Scholar
• Tackmann NR, Zhang Y. Mouse modelling of the MDM2/MDMX-p53 signalling axis. J Mol Cell Biol. 2017;9(1):34–44. doi:10.1093/jmcb/mjx006
   PubMed Web of Science ®Google Scholar
• Wang X, Wang J, Jiang X. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J Biol Chem. 2011;286(27):23725–23734. doi:10.1074/jbc.M110.213868
   PubMed Web of Science ®Google Scholar
• Marine J-C, Jochemsen AG. MDMX (MDM4), a promising target for p53 reactivation therapy and beyond. Cold Spring Harb Perspect Med. 2016;6(7):a026237. doi:10.1101/cshperspect.a026237
   PubMed Web of Science ®Google Scholar
• Haupt S, Mejía-Hernández JO, Vijayakumaran R, Keam SP, Haupt Y. The long and the short of it: the MDM4 tail so far. J Mol Cell Biol. 2019;11(3):231–244. doi:10.1093/jmcb/mjz007
   PubMed Web of Science ®Google Scholar
• Wang S, Zhao Y, Aguilar A, Bernard D, Yang C-Y. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harb Perspect Med. 2017;7(5):a026245. doi:10.1101/cshperspect.a026245
   PubMed Web of Science ®Google Scholar
• Qin -J-J, Li X, Hunt C, Wang W, Wang H, Zhang R. Natural products targeting the p53-MDM2 pathway and mutant p53: recent advances and implications in cancer medicine. Genes Dis. 2018;5(3):204–219. doi:10.1016/j.gendis.2018.07.002
   PubMed Web of Science ®Google Scholar
• Gupta A, Shah K, Oza MJ, Behl T. Reactivation of p53 gene by MDM2 inhibitors: a novel therapy for cancer treatment. Biomed Pharmacother. 2019;109:484–492. doi:10.1016/j.biopha.2018.10.155
   PubMed Web of Science ®Google Scholar
• Popowicz GM, Czarna A, Holak TA. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle. 2008;7(15):2441–2443. doi:10.4161/cc.6365
   PubMed Web of Science ®Google Scholar
• Okamoto K, Kashima K, Pereg Y, et al. DNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent degradation. Mol Cell Biol. 2005;25(21):9608–9620. doi:10.1128/MCB.25.21.9608-9620.2005
   PubMed Web of Science ®Google Scholar
• Shangary S, Qin D, McEachern D, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proc Natl Acad Sci U S A. 2008;105(10):3933–3938. doi:10.1073/pnas.0708917105
   PubMed Web of Science ®Google Scholar
• Huang Q, Chen L, Yang L, et al. MDMX acidic domain inhibits p53 DNA binding in vivo and regulates tumorigenesis. Proc Natl Acad Sci U S A. 2018;115(15):E3368–77. doi:10.1073/pnas.1719090115
   PubMed Web of Science ®Google Scholar
• Chen L, Borcherds W, Wu S, et al. Autoinhibition of MDMX by intramolecular p53 mimicry. Proc Natl Acad Sci U S A. 2015;112(15):4624–4629. doi:10.1073/pnas.1420833112
   PubMed Web of Science ®Google Scholar
• Uchida C, Miwa S, Isobe T, et al. Effects of MdmX on Mdm2-mediated downregulation of pRB. FEBS Lett. 2006;580(7):1753–1758. doi:10.1016/j.febslet.2006.02.029
   PubMed Web of Science ®Google Scholar
• Bista M, Petrovich M, Fersht AR. MDMX contains an autoinhibitory sequence element. Proc Natl Acad Sci U S A. 2013;110(44):17814–17819. doi:10.1073/pnas.1317398110
   PubMed Web of Science ®Google Scholar
• Leslie PL, Ke H, Zhang Y. The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization. J Biol Chem. 2015;290(20):12941–12950. doi:10.1074/jbc.M115.644435
   PubMed Web of Science ®Google Scholar
• Uldrijan S, Pannekoek W-J, Vousden KH. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J. 2007;26(1):102–112. doi:10.1038/sj.emboj.7601469
   PubMed Web of Science ®Google Scholar
• Kawai H, Lopez-Pajares V, Kim MM, Wiederschain D, Yuan Z-M. RING domain-mediated interaction is a requirement for MDM2’s E3 ligase activity. Cancer Res. 2007;67(13):6026–6030. doi:10.1158/0008-5472.CAN-07-1313
   PubMed Web of Science ®Google Scholar
• Koo N, Sharma AK, Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death. Int J Mol Sci. 2022;23(9):5005. doi:10.3390/ijms23095005
   PubMed Web of Science ®Google Scholar
• Toledo F, Wahl GM. MDM2 and MDM4: p53 regulators as targets in anticancer therapy. Int J Biochem Cell Biol. 2007;39(7–8):1476–1482. doi:10.1016/j.biocel.2007.03.022
   PubMed Web of Science ®Google Scholar
• Fu T, Min H, Xu Y, Chen J, Li G. Molecular dynamic simulation insights into the normal state and restoration of p53 function. Int J Mol Sci. 2012;13(8):9709–9740. doi:10.3390/ijms13089709
   PubMed Web of Science ®Google Scholar
• Fang Y, Liao G, Yu B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm Sin B. 2020;10(7):1253–1278. doi:10.1016/j.apsb.2020.01.003
   PubMed Web of Science ®Google Scholar
• Song Q, Liu X-Q, Rainey JK. 1H, 15N and 13C backbone resonance assignments of the acidic domain of the human MDMX protein. Biomol NMR Assign. 2022;16(1):171–178. doi:10.1007/s12104-022-10081-8
   PubMed Web of Science ®Google Scholar
• Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res. 2013;27(4):254–271. doi:10.7555/JBR.27.20130030
   PubMedGoogle Scholar
• Levav-Cohen Y, Goldberg Z, Tan KH, et al. The p53-Mdm2 loop: a critical juncture of stress response. Subcell Biochem. 2014;85:161–186.
   PubMedGoogle Scholar
• Yu D-H, Xu Z-Y, Mo S, Yuan L, Cheng X-D, Qin -J-J. Targeting MDMX for cancer therapy: rationale, strategies, and challenges. Front Oncol. 2020;10:1389. doi:10.3389/fonc.2020.01389
   PubMed Web of Science ®Google Scholar
• Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M. A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res. 1995;23(14):2584–2592. doi:10.1093/nar/23.14.2584
   PubMed Web of Science ®Google Scholar
• Huang L, Yan Z, Liao X, et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci U S A. 2011;108(29):12001–12006. doi:10.1073/pnas.1102309108
   PubMed Web of Science ®Google Scholar
• Chen L, Li C, Pan Y, Chen J. Regulation of p53-MDMX interaction by casein kinase 1 alpha. Mol Cell Biol. 2005;25(15):6509–6520. doi:10.1128/MCB.25.15.6509-6520.2005
   PubMed Web of Science ®Google Scholar
• Di Conza G, Mancini F, Buttarelli M, Pontecorvi A, Trimarchi F, Moretti F. MDM4 enhances p53 stability by promoting an active conformation of the protein upon DNA damage. Cell Cycle. 2012;11(4):749–760. doi:10.4161/cc.11.4.19208
   PubMed Web of Science ®Google Scholar
• Yang J, Jin A, Han J, Chen X, Zheng J, Zhang Y. MDMX recruits UbcH5c to facilitate MDM2 E3 ligase activity and subsequent p53 degradation in vivo. Cancer Res. 2021;81(4):898–909. doi:10.1158/0008-5472.CAN-20-0790
   PubMed Web of Science ®Google Scholar
• Dueber EC, Schoeffler AJ, Lingel A, et al. Antagonists induce a conformational change in cIAP1 that promotes autoubiquitination. Science. 2011;334(6054):376–380. doi:10.1126/science.1207862
   PubMed Web of Science ®Google Scholar
• Linke K, Mace PD, Smith CA, Vaux DL, Silke J, Day CL. Structure of the MDM2/MDMX RING domain heterodimer reveals dimerization is required for their ubiquitylation in trans. Cell Death Differ. 2008;15(5):841–848. doi:10.1038/sj.cdd.4402309
   PubMed Web of Science ®Google Scholar
• Li D, Tavana O, Sun S-C, Gu W. Peli1 modulates the subcellular localization and activity of mdmx. Cancer Res. 2018;78(11):2897–2910. doi:10.1158/0008-5472.CAN-17-3531
   PubMed Web of Science ®Google Scholar
• Pan Y, Chen J. Modification of MDMX by sumoylation. Biochem Biophys Res Commun. 2005;332(3):702–709. doi:10.1016/j.bbrc.2005.05.012
   PubMed Web of Science ®Google Scholar
• Zuckerman V, Lenos K, Popowicz GM, et al. c-Abl phosphorylates Hdmx and regulates its interaction with p53. J Biol Chem. 2009;284(6):4031–4039. doi:10.1074/jbc.M809211200
   PubMed Web of Science ®Google Scholar
• Chen X, Gohain N, Zhan C, Lu W-Y, Pazgier M, Lu W. Structural basis of how stress-induced MDMX phosphorylation activates p53. Oncogene. 2016;35(15):1919–1925. doi:10.1038/onc.2015.255
   PubMed Web of Science ®Google Scholar
• Elias B, Laine A, Ronai Z. Phosphorylation of MdmX by CDK2/Cdc2(p34) is required for nuclear export of Mdm2. Oncogene. 2005;24(15):2574–2579. doi:10.1038/sj.onc.1208488
   PubMed Web of Science ®Google Scholar
• Wu S, Chen L, Becker A, Schonbrunn E, Chen J. Casein kinase 1α regulates an MDMX intramolecular interaction to stimulate p53 binding. Mol Cell Biol. 2012;32(23):4821–4832. doi:10.1128/MCB.00851-12
   PubMed Web of Science ®Google Scholar
• Wei X, Wu S, Song T, et al. Secondary interaction between MDMX and p53 core domain inhibits p53 DNA binding. Proc Natl Acad Sci U S A. 2016;113(19):E2558–2563. doi:10.1073/pnas.1603838113
   PubMed Web of Science ®Google Scholar
• de Polo A, Luo Z, Gerarduzzi C, Chen X, Little JB, Yuan Z-M. AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex. J Mol Cell Biol. 2017;9(2):154–165. doi:10.1093/jmcb/mjw045
   PubMed Web of Science ®Google Scholar
• Wang B, Lim C-B, Yan J, et al. MDMX phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment. J Mol Cell Biol. 2020;12(9):713–722. doi:10.1093/jmcb/mjaa038
   PubMed Web of Science ®Google Scholar
• Swetzig WM, Wang J, Das GM. Estrogen receptor alpha (ERα/ESR1) mediates the p53-independent overexpression of MDM4/MDMX and MDM2 in human breast cancer. Oncotarget. 2016;7(13):16049–16069. doi:10.18632/oncotarget.7533
   PubMedGoogle Scholar
• Bao J, Nanding A, Song H, Xu R, Qu G, Xue Y. The overexpression of MDM4: an effective and novel predictor of gastric adenocarcinoma lymph node metastasis. Oncotarget. 2016;7(41):67212–67222. doi:10.18632/oncotarget.11971
   PubMedGoogle Scholar
• Gao C, Xiao G, Piersigilli A, Gou J, Ogunwobi O, Bargonetti J. Context-dependent roles of MDMX (MDM4) and MDM2 in breast cancer proliferation and circulating tumor cells. Breast Cancer Res. 2019;21(1):5. doi:10.1186/s13058-018-1094-8
   PubMedGoogle Scholar
• Gao C, Xiao G, Bargonetti J. Contemplations on MDMX (MDM4) driving triple negative breast cancer circulating tumor cells and metastasis. Oncotarget. 2019;10(49):5007–5010. doi:10.18632/oncotarget.27134
   PubMedGoogle Scholar
• Bauer M, Kantelhardt EJ, Stiewe T, et al. Specific allelic variants of SNPs in the MDM2 and MDMX genes are associated with earlier tumor onset and progression in Caucasian breast cancer patients. Oncotarget. 2019;10(20):1975–1992. doi:10.18632/oncotarget.26768
   PubMedGoogle Scholar
• Gilkes DM, Pan Y, Coppola D, Yeatman T, Reuther GW, Chen J. Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol. 2008;28(6):1999–2010. doi:10.1128/MCB.01633-07
   PubMed Web of Science ®Google Scholar
• Suda T, Yoshihara M, Nakamura Y, et al. Rare MDM4 gene amplification in colorectal cancer: the principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable. Oncol Rep. 2011;26(1):49–54. doi:10.3892/or.2011.1270
   PubMed Web of Science ®Google Scholar
• Karki A, Putra J, Kim SS, et al. MDM4 expression in fibrolamellar hepatocellular carcinoma. Oncol Rep. 2019;42(4):1487–1496. doi:10.3892/or.2019.7241
   PubMed Web of Science ®Google Scholar
• Gembarska A, Luciani F, Fedele C, et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012;18(8):1239–1247. doi:10.1038/nm.2863
   PubMed Web of Science ®Google Scholar
• Chopra H, Khan Z, Contreras J, Wang H, Sedrak A, Zhu Y. Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells. Oncotarget. 2018;9(5):6270–6281. doi:10.18632/oncotarget.23569
   PubMedGoogle Scholar
• Ueda K, Kumari R, Schwenger E, et al. MDMX acts as a pervasive preleukemic-to-acute myeloid leukemia transition mechanism. Cancer Cell. 2021;39(4):529–547.e7. doi:10.1016/j.ccell.2021.02.006
   PubMed Web of Science ®Google Scholar
• Leventaki V, Rodic V, Tripp SR, et al. TP 53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. Br J Haematol. 2012;158(6):763–771. doi:10.1111/j.1365-2141.2012.09243.x
   PubMed Web of Science ®Google Scholar
• Zhang J, Schweers B, Dyer MA. The first knockout mouse model of retinoblastoma. Cell Cycle. 2004;3(7):952–959. doi:10.4161/cc.3.7.1002
   PubMed Web of Science ®Google Scholar
• Laurie NA, Donovan SL, Shih C-S, et al. Inactivation of the p53 pathway in retinoblastoma. Nature. 2006;444:61–66. doi:10.1038/nature05194
   PubMed Web of Science ®Google Scholar
• Zhao H, Xie Y-Z, Xing R, Sun M, Chi F, Zeng Y-C. MDMX is a prognostic factor for non-small cell lung cancer and regulates its sensitivity to cisplatin. Cell Oncol. 2017;40(4):357–365. doi:10.1007/s13402-017-0325-9
   Web of Science ®Google Scholar
• Han X, Garcia-Manero G, McDonnell TJ, et al. HDM4 (HDMX) is widely expressed in adult pre-B acute lymphoblastic leukemia and is a potential therapeutic target. Mod Pathol. 2007;20(1):54–62. doi:10.1038/modpathol.3800727
   PubMed Web of Science ®Google Scholar
• Valentin-Vega YA, Barboza JA, Chau GP, El-Naggar AK, Lozano G. High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas. Hum Pathol. 2007;38(10):1553–1562. doi:10.1016/j.humpath.2007.03.005
   PubMed Web of Science ®Google Scholar
• Sinatkas V, Stathopoulou K, Xagoraris I, et al. MDMX/MDM4 is highly expressed and contributes to cell growth and survival in anaplastic large cell lymphoma. Leuk Lymphoma. 2021;62(7):1563–1573. doi:10.1080/10428194.2021.1876871
   PubMed Web of Science ®Google Scholar
• Ach T, Schwarz-Furlan S, Ach S, et al. Genomic aberrations of MDM2, MDM4, FGFR1 and FGFR3 are associated with poor outcome in patients with salivary gland cancer. J Oral Pathol Med. 2016;45(7):500–509. doi:10.1111/jop.12394
   PubMed Web of Science ®Google Scholar
• Fan Y, Li M, Ma K, et al. Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway. Cancer Biol Ther. 2019;20(5):617–632. doi:10.1080/15384047.2018.1539290
   PubMed Web of Science ®Google Scholar
• Busuttil RA, Zapparoli GV, Haupt S, et al. Role of p53 in the progression of gastric cancer. Oncotarget. 2014;5(23):12016–12026. doi:10.18632/oncotarget.2434
   PubMedGoogle Scholar
• Wang X, Yamamoto Y, Imanishi M, et al. Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild-type TP53 colon and gastric cancer cells with aberrant KRAS signaling. Oncol Lett. 2021;22(1):558. doi:10.3892/ol.2021.12819
   PubMed Web of Science ®Google Scholar
• Dewaele M, Tabaglio T, Willekens K, et al. Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth. J Clin Invest. 2016;126(1):68–84. doi:10.1172/JCI82534
   PubMed Web of Science ®Google Scholar
• Arnoff TE, El-Deiry WS. MDM2/MDM4 amplification and CDKN2A deletion in metastatic melanoma and glioblastoma multiforme may have implications for targeted therapeutics and immunotherapy. Am J Cancer Res. 2022;12(5):2102–2117.
   PubMed Web of Science ®Google Scholar
• Stegeman S, Moya L, Selth LA, Spurdle AB, Clements JA, Batra J. A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer. Endocr Relat Cancer. 2015;22(2):265–276. doi:10.1530/ERC-15-0013
   PubMed Web of Science ®Google Scholar
• Mejía-Hernández JO, Raghu D, Caramia F, et al. Targeting MDM4 as a novel therapeutic approach in prostate cancer independent of p53 status. Cancers. 2022;14(16):3947. doi:10.3390/cancers14163947
   PubMed Web of Science ®Google Scholar
• Wang D, Zhang S, Zhao M, Chen F. LncRNA MALAT1 accelerates non-small cell lung cancer progression via regulating miR-185-5p/MDM4 axis. Cancer Med. 2020;9(23):9138–9149. doi:10.1002/cam4.3570
   PubMed Web of Science ®Google Scholar
• Ally A, Balasundaram M, Carlsen R; The Cancer Genome Atlas Research Network. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell. 2017;169(7):1327–1341.e23. doi:10.1016/j.cell.2017.05.046
   PubMed Web of Science ®Google Scholar
• Pellegrino R, Calvisi DF, Neumann O, et al. EEF1A2 inactivates p53 by way of PI3K/AKT/mTOR-dependent stabilization of MDM4 in hepatocellular carcinoma. Hepatology. 2014;59(5):1886–1899. doi:10.1002/hep.26954
   PubMed Web of Science ®Google Scholar
• Pellegrino R, Thavamani A, Calvisi DF, et al. Serum Response Factor (SRF) drives the transcriptional upregulation of the MDM4 oncogene in HCC. Cancers. 2021;13(2):199. doi:10.3390/cancers13020199
   PubMed Web of Science ®Google Scholar
• Ten Kate FJC, Suzuki L, Dorssers LCJ, et al. Pattern of p53 protein expression is predictive for survival in chemoradiotherapy-naive esophageal adenocarcinoma. Oncotarget. 2017;8(61):104123–104135. doi:10.18632/oncotarget.22021
   PubMedGoogle Scholar
• Jiang K, Sun F, Zhu J, Luo G, Ban Y, Zhang P. miR-33a inhibits cell growth in renal cancer by downregulation of MDM4 expression. Mol Genet Genomic Med. 2019;7(8):e833. doi:10.1002/mgg3.833
   PubMed Web of Science ®Google Scholar
• Gansmo LB, Bjørnslett M, Halle MK, et al. The MDM4 SNP34091 (rs4245739) C-allele is associated with increased risk of ovarian-but not endometrial cancer. Tumour Biol. 2016;37(8):10697–10702. doi:10.1007/s13277-016-4940-2
   PubMedGoogle Scholar
• Hu W, Feng Z, Modica I, et al. Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway. Genes Cancer. 2010;1(4):360–368. doi:10.1177/1947601910371979
   PubMedGoogle Scholar
• Feeley KP, Adams CM, Mitra R, Eischen CM. Mdm2 is required for survival and growth of p53-deficient cancer cells. Cancer Res. 2017;77(14):3823–3833. doi:10.1158/0008-5472.CAN-17-0809
   PubMed Web of Science ®Google Scholar
• Matijasevic Z, Steinman HA, Hoover K, Jones SN. MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice. Mol Cell Biol. 2008;28(4):1265–1273. doi:10.1128/MCB.01108-07
   PubMed Web of Science ®Google Scholar
• Matijasevic Z, Krzywicka-Racka A, Sluder G, Gallant J, Jones SN. The Zn-finger domain of MdmX suppresses cancer progression by promoting genome stability in p53-mutant cells. Oncogenesis. 2016;5(10):e262. doi:10.1038/oncsis.2016.62
   PubMedGoogle Scholar
• Xiong S, Pant V, Zhang Y, et al. The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis. J Pathol. 2017;241(4):501–510. doi:10.1002/path.4854
   PubMed Web of Science ®Google Scholar
• Zhang H, Hu L, Qiu W, et al. MDMX exerts its oncogenic activity via suppression of retinoblastoma protein. Oncogene. 2015;34(44):5560–5569. doi:10.1038/onc.2015.11
   PubMed Web of Science ®Google Scholar
• Klein AM, Biderman L, Tong D, et al. MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53. Proc Natl Acad Sci U S A. 2021;118(44):e2102420118. doi:10.1073/pnas.2102420118
   PubMed Web of Science ®Google Scholar
• Carrillo AM, Bouska A, Arrate MP, Eischen CM. Mdmx promotes genomic instability independent of p53 and Mdm2. Oncogene. 2015;34(7):846–856. doi:10.1038/onc.2014.27
   PubMed Web of Science ®Google Scholar
• Wohlberedt K, Klusmann I, Derevyanko PK, et al. Mdm4 supports DNA replication in a p53-independent fashion. Oncogene. 2020;39(25):4828–4843. doi:10.1038/s41388-020-1325-1
   PubMed Web of Science ®Google Scholar
• Holzer P, Masuya K, Furet P, et al. Discovery of a dihydroisoquinolinone derivative (NVP-CGM097): a highly potent and selective MDM2 inhibitor undergoing Phase 1 clinical trials in p53wt tumors. J Med Chem. 2015;58(16):6348–6358. doi:10.1021/acs.jmedchem.5b00810
   PubMed Web of Science ®Google Scholar
• Konopleva M, Martinelli G, Daver N, et al. MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020;34(11):2858–2874. doi:10.1038/s41375-020-0949-z
   PubMed Web of Science ®Google Scholar
• Bista M, Smithson D, Pecak A, et al. On the mechanism of action of SJ-172550 in inhibiting the interaction of MDM4 and p53. PLoS One. 2012;7(6):e37518. doi:10.1371/journal.pone.0037518
   PubMed Web of Science ®Google Scholar
• Karan G, Wang H, Chakrabarti A, et al. Identification of a small molecule that overcomes HdmX-mediated suppression of p53. Mol Cancer Ther. 2016;15(4):574–582. doi:10.1158/1535-7163.MCT-15-0467
   PubMed Web of Science ®Google Scholar
• Ilic VK, Egorova O, Tsang E, et al. Hinokiflavone inhibits MDM2 activity by targeting the MDM2-MDMX RING domain. Biomolecules. 2022;12(5):643. doi:10.3390/biom12050643
   PubMed Web of Science ®Google Scholar
• Boltjes A, Huang Y, van de Velde R, et al. Fragment-based library generation for the discovery of a peptidomimetic p53-Mdm4 inhibitor. ACS Comb Sci. 2014;16(8):393–396. doi:10.1021/co500026b
   PubMed Web of Science ®Google Scholar
• Uesato S, Matsuura Y, Matsue S, et al. Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities. Bioorg Med Chem. 2016;24(8):1919–1926. doi:10.1016/j.bmc.2016.03.021
   PubMed Web of Science ®Google Scholar
• Jiang L, Malik N, Acedo P, Zawacka-Pankau J. Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukemia cells. Cell Death Discov. 2019;5:77. doi:10.1038/s41420-019-0157-7
   PubMed Web of Science ®Google Scholar
• Graves B, Thompson T, Xia M, et al. Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization. Proc Natl Acad Sci U S A. 2012;109(29):11788–11793. doi:10.1073/pnas.1203789109
   PubMed Web of Science ®Google Scholar
• Pishas KI, Adwal A, Neuhaus SJ, et al. XI-006 induces potent p53-independent apoptosis in Ewing sarcoma. Sci Rep. 2015;5(1):11465. doi:10.1038/srep11465
   PubMedGoogle Scholar
• Wang H, Yan C. A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells. Neoplasia. 2011;13(7):611–619. doi:10.1593/neo.11438
   PubMed Web of Science ®Google Scholar
• Voruganti S, Qin -J-J, Sarkar S, et al. Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action. Oncotarget. 2015;6(25):21379–21394. doi:10.18632/oncotarget.4091
   PubMedGoogle Scholar
• Gerhart SV, Kellner WA, Thompson C, et al. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci Rep. 2018;8(1):9711. doi:10.1038/s41598-018-28002-y
   PubMed Web of Science ®Google Scholar
• Qin -J-J, Li X, Wang W, Zi X, Zhang R. Targeting the NFAT1-MDM2-MDMX network inhibits the proliferation and invasion of prostate cancer cells, independent of p53 and androgen. Front Pharmacol. 2017;8:917. doi:10.3389/fphar.2017.00917
   PubMed Web of Science ®Google Scholar
• Vaseva AV, Yallowitz AR, Marchenko ND, Xu S, Moll UM. Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors. Cell Death Dis. 2011;2(5):e156. doi:10.1038/cddis.2011.39
   PubMedGoogle Scholar
• Pairawan S, Zhao M, Yuca E, et al. First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models. Breast Cancer Res. 2021;23(1):29. doi:10.1186/s13058-021-01406-x
   PubMed Web of Science ®Google Scholar
• Saleh MN, Patel MR, Bauer TM, et al. Phase 1 trial of ALRN-6924, a dual inhibitor of MDMX and MDM2, in patients with solid tumors and lymphomas bearing wild-type TP53. Clin Cancer Res. 2021;27(19):5236–5247. doi:10.1158/1078-0432.CCR-21-0715
   PubMed Web of Science ®Google Scholar
• Tisato V, Voltan R, Gonelli A, Secchiero P, Zauli G. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer. J Hematol Oncol. 2017;10(1):133. doi:10.1186/s13045-017-0500-5
   PubMed Web of Science ®Google Scholar
• Espadinha M, Barcherini V, Lopes EA, Santos MMM. An Update on MDMX and Dual MDM2/X Inhibitors. Curr Top Med Chem. 2018;18(8):647–660. doi:10.2174/1568026618666180604080119
   PubMed Web of Science ®Google Scholar
• Wang H, Ma X, Ren S, Buolamwini JK, Yan C. A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Mol Cancer Ther. 2011;10(1):69–79. doi:10.1158/1535-7163.MCT-10-0581
   PubMed Web of Science ®Google Scholar
• Jiang Z-Q, M-H L, Qin Y-M, Jiang H-Y, Zhang X, Wu M-H. Luteolin inhibits tumorigenesis and induces apoptosis of non-small cell lung cancer cells via regulation of microRNA-34a-5p. Int J Mol Sci. 2018;19(2):447. doi:10.3390/ijms19020447
   PubMed Web of Science ®Google Scholar
• Zu Y, Wang J, Ping W, Sun W. Tan IIA inhibits H1299 cell viability through the MDM4‑IAP3 signaling pathway. Mol Med Rep. 2018;17(2):2384–2392. doi:10.3892/mmr.2017.8152
   PubMed Web of Science ®Google Scholar
• Wang W, Qin -J-J, Li X, et al. Prevention of prostate cancer by natural product MDM2 inhibitor GS25: in vitro and in vivo activities and molecular mechanisms. Carcinogenesis. 2018;39(8):1026–1036. doi:10.1093/carcin/bgy063
   PubMed Web of Science ®Google Scholar
• Bezzi M, Teo SX, Muller J, et al. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 2013;27(17):1903–1916. doi:10.1101/gad.219899.113
   PubMed Web of Science ®Google Scholar
• Ling X, Xu C, Fan C, Zhong K, Li F, Wang X. FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX. Cancer Res. 2014;74(24):7487–7497. doi:10.1158/0008-5472.CAN-14-0683
   PubMed Web of Science ®Google Scholar
• Zheng X, Yan J, You W, et al. De novo nano-erythrocyte structurally braced by biomimetic Au(I)-peptide Skeleton for MDM2/MDMX predation toward augmented pulmonary adenocarcinoma immunotherapy. Small. 2021;17(20):e2100394. doi:10.1002/smll.202100394
   PubMed Web of Science ®Google Scholar
• El-Deiry WS, Arnoff T, Sahin I, et al. A pancancer analysis of impact of MDM2/MDM4 on immune checkpoint blockade (ICB). JCO. 2022;40(16_suppl):2630. doi:10.1200/JCO.2022.40.16_suppl.2630
   Web of Science ®Google Scholar
• Cheng J, Li Y, Wang X, et al. Response stratification in the first-line combined immunotherapy of hepatocellular carcinoma at genomic, transcriptional and immune repertoire levels. J Hepatocell Carcinoma. 2021;8:1281–1295. doi:10.2147/JHC.S326356
   PubMed Web of Science ®Google Scholar
• Fang W, Zhou H, Shen J, et al. MDM2/4 amplification predicts poor response to immune checkpoint inhibitors: a pan-cancer analysis. ESMO Open. 2020;5(1):4. doi:10.1136/esmoopen-2019-000614
   Web of Science ®Google Scholar
• Graveley BR. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. 2001;17(2):100–107. doi:10.1016/S0168-9525(00)02176-4
   PubMed Web of Science ®Google Scholar
• Bardot B, Toledo F. Targeting MDM4 Splicing in Cancers. Genes (Basel). 2017;8(2):82. doi:10.3390/genes8020082
   PubMed Web of Science ®Google Scholar
• Grawenda AM, Møller EK, Lam S, et al. Interaction between p53 mutation and a somatic HDMX biomarker better defines metastatic potential in breast cancer. Cancer Res. 2015;75(4):698–708. doi:10.1158/0008-5472.CAN-14-2637
   PubMed Web of Science ®Google Scholar
• Bartel F, Schulz J, Böhnke A, et al. Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis. Int J Cancer. 2005;117(3):469–475. doi:10.1002/ijc.21206
   PubMed Web of Science ®Google Scholar
• Lenos K, Grawenda AM, Lodder K, et al. Alternate splicing of the p53 inhibitor HDMX offers a superior prognostic biomarker than p53 mutation in human cancer. Cancer Res. 2012;72(16):4074–4084. doi:10.1158/0008-5472.CAN-12-0215
   PubMed Web of Science ®Google Scholar
• Liu L, Fan L, Fang C, et al. S-MDM4 mRNA overexpression indicates a poor prognosis and marks a potential therapeutic target in chronic lymphocytic leukemia. Cancer Sci. 2012;103(12):2056–2063. doi:10.1111/cas.12008
   PubMed Web of Science ®Google Scholar
• Liang M, Han X, Vadhan-Raj S, et al. HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis. Mod Pathol. 2010;23(3):381–391. doi:10.1038/modpathol.2009.170
   PubMed Web of Science ®Google Scholar
• Pant V, Larsson CA, Aryal N, et al. Tumorigenesis promotes Mdm4-S overexpression. Oncotarget. 2017;8(16):25837–25847. doi:10.18632/oncotarget.15552
   PubMedGoogle Scholar
• Giglio S, Mancini F, Gentiletti F, et al. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer Res. 2005;65(21):9687–9694. doi:10.1158/0008-5472.CAN-05-0450
   PubMed Web of Science ®Google Scholar
• de Graaf P, Little NA, Ramos YFM, Meulmeester E, Letteboer SJF, Jochemsen AG. Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2. J Biol Chem. 2003;278(40):38315–38324. doi:10.1074/jbc.M213034200
   PubMed Web of Science ®Google Scholar
• Bykov VJN, Eriksson SE, Bianchi J, Wiman KG. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer. 2018;18(2):89–102. doi:10.1038/nrc.2017.109
   PubMed Web of Science ®Google Scholar
• Rallapalli R, Strachan G, Tuan RS, Hall DJ. Identification of a domain within MDMX-S that is responsible for its high affinity interaction with p53 and high-level expression in mammalian cells. J Cell Biochem. 2003;89(3):563–575. doi:10.1002/jcb.10535
   PubMed Web of Science ®Google Scholar
• Mancini F, Pieroni L, Monteleone V, et al. MDM4/HIPK2/p53 cytoplasmic assembly uncovers coordinated repression of molecules with anti-apoptotic activity during early DNA damage response. Oncogene. 2016;35(2):228–240. doi:10.1038/onc.2015.76
   PubMed Web of Science ®Google Scholar
• Pazgier M, Liu M, Zou G, et al. Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX. Proc Natl Acad Sci U S A. 2009;106(12):4665–4670. doi:10.1073/pnas.0900947106
   PubMed Web of Science ®Google Scholar