Mouse Models of Mdm2 and Mdm4 and Their Clinical Implications

Overview

Journal Chin J Cancer

Publisher Biomed Central

Specialty Oncology

Date 2013 Jan 19

PMID 23327795

Citations 11

Authors

Shunbin Xiong

Affiliations

Soon will be listed here.

Abstract

Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53. Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models. The tissue-specific deletion of Mdm2 induces p53-dependent apoptosis, whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest. Compared to Mdm4 deletion, Mdm2 deletion causes more severe phenotypic defects. Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53, suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis. Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis, which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes. Studies from these mouse models strongly suggest that blocking Mdm2- and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.

Citing Articles

SETBP1 activation upon MDM4-enhanced ubiquitination of NR3C1 triggers dissemination of colorectal cancer cells.

Zhai P, Zhang H, Li Q, Hu Z, Zhang H, Yang M Clin Exp Metastasis. 2024; 41(5):747-764.

PMID: 38796806 DOI: 10.1007/s10585-024-10294-2.

Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?.

Thomas A, Kelly G, Strasser A Cell Death Differ. 2022; 29(5):961-971.

PMID: 35396345 PMC: 9090748. DOI: 10.1038/s41418-022-00996-z.

The development of the concept of ferroptosis.

Hirschhorn T, Stockwell B Free Radic Biol Med. 2018; 133:130-143.

PMID: 30268886 PMC: 6368883. DOI: 10.1016/j.freeradbiomed.2018.09.043.

Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers.

Katz C, Low-Calle A, Choe J, Laptenko O, Tong D, Joseph-Chowdhury J Genes Dev. 2018; 32(5-6):430-447.

PMID: 29549180 PMC: 5900715. DOI: 10.1101/gad.304071.117.

Cardiac-specific ablation of the E3 ubiquitin ligase Mdm2 leads to oxidative stress, broad mitochondrial deficiency and early death.

Hauck L, Stanley-Hasnain S, Fung A, Grothe D, Rao V, Mak T PLoS One. 2017; 12(12):e0189861.

PMID: 29267372 PMC: 5739440. DOI: 10.1371/journal.pone.0189861.

References

Pant V, Xiong S, Iwakuma T, Quintas-Cardama A, Lozano G . Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc Natl Acad Sci U S A. 2011; 108(29):11995-2000. PMC: 3141986. DOI: 10.1073/pnas.1102241108. 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

Grier J, Xiong S, Elizondo-Fraire A, Parant J, Lozano G . Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol Cell Biol. 2005; 26(1):192-8. PMC: 1317622. DOI: 10.1128/MCB.26.1.192-198.2006. View

Valentin-Vega Y, Barboza J, Chau G, El-Naggar A, Lozano G . High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas. Hum Pathol. 2007; 38(10):1553-62. PMC: 2699677. DOI: 10.1016/j.humpath.2007.03.005. View

Vassilev L, Vu B, Graves B, Carvajal D, Podlaski F, Filipovic Z . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303(5659):844-8. DOI: 10.1126/science.1092472. View

Zhou M, Yeager A, Smith S, Findley H . Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene. Blood. 1995; 85(6):1608-14. View

Xiong S, Van Pelt C, Elizondo-Fraire A, Fernandez-Garcia B, Lozano G . Loss of Mdm4 results in p53-dependent dilated cardiomyopathy. Circulation. 2007; 115(23):2925-30. DOI: 10.1161/CIRCULATIONAHA.107.689901. View

Marine J, Jochemsen A . Mdmx and Mdm2: brothers in arms?. Cell Cycle. 2004; 3(7):900-4. View

Ramos Y, Stad R, Attema J, Peltenburg L, Van Der Eb A, Jochemsen A . Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res. 2001; 61(5):1839-42. View

10.

Onel K, Cordon-Cardo C . MDM2 and prognosis. Mol Cancer Res. 2004; 2(1):1-8. View

11.

Shangary S, Qin D, McEachern D, Liu M, Miller R, Qiu S . 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):3933-8. PMC: 2268798. DOI: 10.1073/pnas.0708917105. View

12.

Wade M, Wahl G . Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?. Mol Cancer Res. 2009; 7(1):1-11. PMC: 2629357. DOI: 10.1158/1541-7786.MCR-08-0423. View

13.

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

14.

Garcia D, Warr M, Martins C, Swigart L, Passegue E, Evan G . Validation of MdmX as a therapeutic target for reactivating p53 in tumors. Genes Dev. 2011; 25(16):1746-57. PMC: 3165938. DOI: 10.1101/gad.16722111. View

15.

Duan W, Gao L, Druhan L, Zhu W, Morrison C, Otterson G . Expression of Pirh2, a newly identified ubiquitin protein ligase, in lung cancer. J Natl Cancer Inst. 2004; 96(22):1718-21. DOI: 10.1093/jnci/djh292. View

16.

Wang Y, Wade M, Wong E, Li Y, Rodewald L, Wahl G . Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation. Proc Natl Acad Sci U S A. 2007; 104(30):12365-70. PMC: 1941475. DOI: 10.1073/pnas.0701497104. View

17.

Bernal F, Wade M, Godes M, Davis T, Whitehead D, Kung A . A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. 2010; 18(5):411-22. PMC: 3050021. DOI: 10.1016/j.ccr.2010.10.024. View

18.

Xiong S, Pant V, Suh Y, Van Pelt C, Wang Y, Valentin-Vega Y . Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res. 2010; 70(18):7148-54. PMC: 2940952. DOI: 10.1158/0008-5472.CAN-10-1457. View

19.

Riemenschneider M, Buschges R, Wolter M, Reifenberger J, Bostrom J, Kraus J . Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res. 2000; 59(24):6091-6. View

20.

Grier J, Yan W, Lozano G . Conditional allele of mdm2 which encodes a p53 inhibitor. Genesis. 2002; 32(2):145-7. DOI: 10.1002/gene.10066. View