MDM4 Expression As an Indicator of TP53 Reactivation by Combined Targeting of MDM2 and MDM4 in Cancer Cells Without TP53 Mutation

Overview

Journal Oncoscience

Specialty Oncology

Date 2015 Jan 27

PMID 25621298

Citations 8

Authors

Mitsuaki Hirose

Kenji Yamato

Shinji Endo

Rie Saito

Takunori Ueno

Sachiko Hirai

Hideo Suzuki

Masato Abei

Yukikazu Natori

Ichinosuke Hyodo

Affiliations

Soon will be listed here.

Abstract

MDM2 and MDM4, a structurally related MDM2 homolog, negatively regulates expression and functions of TP53 tumor suppressor gene. To explore the precise expression patterns and function of MDM2 and MDM4 in wild-type (wt) TP53 cancer cells, we analyzed 11 various cancer cell lines with wt TP53. All cell lines exhibited deregulated expression of MDM2 and MDM4, and were divided into two distinct types; the one expressing high levels of MDM4 and another expressing low levels of MDM4. The low MDM4 type expressed higher MDM2 levels than the high MDM4 type. In cells with high MDM4 expression, knockdown of MDM4 or MDM2 reactivated TP53, and simultaneous knockdown of MDM2 and MDM4 synergistically reactivated TP53. In contrast, in cells with low MDM4 expression, knockdown of only MDM2 reactivated TP53. These results suggest that both MDM2 and MDM4 are closely involved in TP53 inactivation in cancer cells with high MDM4 expression, whereas only MDM2, and not MDM4, is a regulator of TP53 in cells with low MDM4 expression. MDM4 expression in wt TP53-tumors is a potential indicator for TP53 reactivation cancer therapy by simultaneous targeting of MDM4 and MDM2. Specific knockdown of MDM2 and MDM4 might be applicable for TP53 restoration therapy.

Citing Articles

Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild-type colon and gastric cancer cells with aberrant KRAS signaling.

Wang X, Yamamoto Y, Imanishi M, Zhang X, Sato M, Sugaya A Oncol Lett. 2021; 22(1):558.

PMID: 34084225 PMC: 8161467. DOI: 10.3892/ol.2021.12819.

MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 Degradation .

Yang J, Jin A, Han J, Chen X, Zheng J, Zhang Y Cancer Res. 2020; 81(4):898-909.

PMID: 33277368 PMC: 8026549. DOI: 10.1158/0008-5472.CAN-20-0790.

Identification of selective protein-protein interaction inhibitors using efficient peptide-directed ligand design.

Beekman A, Cominetti M, Walpole S, Prabhu S, OConnell M, Angulo J Chem Sci. 2019; 10(16):4502-4508.

PMID: 31057779 PMC: 6482886. DOI: 10.1039/c9sc00059c.

Augmented antitumor activity of 5-fluorouracil by double knockdown of MDM4 and MDM2 in colon and gastric cancer cells.

Imanishi M, Yamamoto Y, Wang X, Sugaya A, Hirose M, Endo S Cancer Sci. 2018; 110(2):639-649.

PMID: 30488540 PMC: 6361612. DOI: 10.1111/cas.13893.

p53 Is Active in Human Amniotic Fluid Stem Cells.

Rodrigues M, Antonucci I, Elabd S, Kancherla S, Marchisio M, Blattner C Stem Cells Dev. 2018; 27(21):1507-1517.

PMID: 30044176 PMC: 6209428. DOI: 10.1089/scd.2017.0254.

References

Coelho T, Adams D, Silva A, Lozeron P, Hawkins P, Mant T . Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013; 369(9):819-29. DOI: 10.1056/NEJMoa1208760. View

Chen C, Ridzon D, Broomer A, Zhou Z, Lee D, Nguyen J . Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005; 33(20):e179. PMC: 1292995. DOI: 10.1093/nar/gni178. View

Martin K, Trouche D, Hagemeier C, Sorensen T, La Thangue N, Kouzarides T . Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. Nature. 1995; 375(6533):691-4. DOI: 10.1038/375691a0. View

Naito Y, Yamada T, Ui-Tei K, Morishita S, Saigo K . siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Res. 2004; 32(Web Server issue):W124-9. PMC: 441580. DOI: 10.1093/nar/gkh442. View

Gilkes D, Pan Y, Coppola D, Yeatman T, Reuther G, Chen J . Regulation of MDMX expression by mitogenic signaling. Mol Cell Biol. 2008; 28(6):1999-2010. PMC: 2268405. DOI: 10.1128/MCB.01633-07. View

Wade M, Wang Y, Wahl G . The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol. 2010; 20(5):299-309. PMC: 2910097. DOI: 10.1016/j.tcb.2010.01.009. View

Migliorini D, Danovi D, Colombo E, Carbone R, Pelicci P, Marine J . Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. J Biol Chem. 2001; 277(9):7318-23. DOI: 10.1074/jbc.M108795200. View

Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, Jochemsen A . Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem. 2002; 277(22):19251-4. DOI: 10.1074/jbc.C200150200. View

Pan Y, Chen J . MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol. 2003; 23(15):5113-21. PMC: 165735. DOI: 10.1128/MCB.23.15.5113-5121.2003. View

10.

Gembarska A, Luciani F, Fedele C, Russell E, Dewaele M, Villar S . MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med. 2012; 18(8):1239-47. PMC: 3744207. DOI: 10.1038/nm.2863. View

11.

Jin Y, Lee H, Zeng S, Dai M, Lu H . MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 2003; 22(23):6365-77. PMC: 291841. DOI: 10.1093/emboj/cdg600. View

12.

Castanotto D, Sakurai K, Lingeman R, Li H, Shively L, Aagaard L . Combinatorial delivery of small interfering RNAs reduces RNAi efficacy by selective incorporation into RISC. Nucleic Acids Res. 2007; 35(15):5154-64. PMC: 1976469. DOI: 10.1093/nar/gkm543. View

13.

Shvarts A, Steegenga W, Riteco N, van Laar T, Dekker P, Bazuine M . MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 1996; 15(19):5349-57. PMC: 452278. View

14.

Ringshausen I, OShea C, Finch A, Swigart L, Evan G . Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell. 2006; 10(6):501-14. DOI: 10.1016/j.ccr.2006.10.010. View

15.

Laurie N, Donovan S, Shih C, Zhang J, Mills N, Fuller C . Inactivation of the p53 pathway in retinoblastoma. Nature. 2006; 444(7115):61-6. DOI: 10.1038/nature05194. View

16.

Hu B, Gilkes D, Farooqi B, Sebti S, Chen J . MDMX overexpression prevents p53 activation by the MDM2 inhibitor Nutlin. J Biol Chem. 2006; 281(44):33030-5. DOI: 10.1074/jbc.C600147200. View

17.

FitzGerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt B, Sutherland J . Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2013; 383(9911):60-68. PMC: 4387547. DOI: 10.1016/S0140-6736(13)61914-5. View

18.

Pant V, Lozano G . Dissecting the p53-Mdm2 feedback loop in vivo: uncoupling the role in p53 stability and activity. Oncotarget. 2014; 5(5):1149-56. PMC: 4012731. DOI: 10.18632/oncotarget.1797. View

19.

Chou T, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984; 22:27-55. DOI: 10.1016/0065-2571(84)90007-4. View

20.

Forbes S, Bindal N, Bamford S, Cole C, Kok C, Beare D . COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2010; 39(Database issue):D945-50. PMC: 3013785. DOI: 10.1093/nar/gkq929. View