Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability

Proceedings of the National Academy of Sciences of the United States of America

Volumn 108, Issue 29, 2011, Pages 11995-12000

  Pant, Vinod ^a   Xiong, Shunbin ^a   Iwakuma, Tomoo ^b   Quintaś Cardama, Alfonso ^a   Lozano, Guillermina ^a  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b LOUISIANA STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Mdmx; Mouse models; p53 stability; Ubiquitination

Indexed keywords

PROTEIN MDM2; PROTEIN MDMX; PROTEIN P53;

ALLELE; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DIMERIZATION; EMBRYO; EMBRYO DEVELOPMENT; GENE DELETION; HETEROZYGOSITY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN INTERACTION;

ANIMALS; BLOTTING, SOUTHERN; CESIUM RADIOISOTOPES; DNA PRIMERS; EMBRYONIC DEVELOPMENT; GENE EXPRESSION REGULATION, DEVELOPMENTAL; GENOTYPE; MICE; MICE, TRANSGENIC; PROTEIN MULTIMERIZATION; PROTO-ONCOGENE PROTEINS; PROTO-ONCOGENE PROTEINS C-MDM2; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; TUMOR SUPPRESSOR PROTEIN P53; UBIQUITIN-PROTEIN LIGASES; UBIQUITINATION;

EID: 79961039603     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1102241108     Document Type: Article

References (38)

1. Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated trans-activation. Cell 69:1237-1245.
2. Shvarts A, et al. (1996) MDMX: A novel p53-binding protein with some functional properties of MDM2. EMBO J 15:5349-5357. (Pubitemid 26336217)
3. Marine JC, Dyer MA, Jochemsen AG (2007) MDMX: From bench to bedside. J Cell Sci 120:371-378. (Pubitemid 46332500)
4. Montes de Oca Luna R, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378:203-206.
5. Jones SN, Roe AE, Donehower LA, Bradley A (1995) Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378:206-208.
6. Parant J, et al. (2001) Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nat Genet 29:92-95. (Pubitemid 32801817)
7. Migliorini D, et al. (2002) Mdm4 (Mdmx) regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development. Mol Cell Biol 22:5527-5538. (Pubitemid 34755762)
8. Finch RA, et al. (2002) mdmx is a negative regulator of p53 activity in vivo. Cancer Res 62:3221-3225. (Pubitemid 34602417)
9. Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296-299. (Pubitemid 27220766)
10. Honda R, Tanaka H, Yasuda H (1997) Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett 420:25-27. (Pubitemid 28037193)
11. Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387:299-303. (Pubitemid 27220767)
12. Haines DS, Landers JE, Engle LJ, George DL (1994) Physical and functional interaction between wild-type p53 and mdm2 proteins. Mol Cell Biol 14:1171-1178. (Pubitemid 24036568)
13. Tanimura S, et al. (1999) MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 447:5-9. (Pubitemid 29134936)
14. Pan Y, Chen J (2003) MDM2 promotes ubiquitination and degradation of MDMX. Mol Cell Biol 23:5113-5121. (Pubitemid 36950868)
15. Kawai H, Lopez-Pajares V, Kim MM, Wiederschain D, Yuan ZM (2007) RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity. Cancer Res 67: 6026-6030. (Pubitemid 47037481)
16. Okamoto K, Taya Y, Nakagama H (2009) Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. FEBS Lett 583:2710-2714.
17. Grier JD, Xiong S, Elizondo-Fraire AC, Parant JM, Lozano G (2006) Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4. Mol Cell Biol 26:192-198.
18. Lang GA, et al. (2004) Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861-872. (Pubitemid 40017691)
19. Terzian T, et al. (2008) The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev 22:1337-1344. (Pubitemid 351717524)
20. Cheng Q, Chen J (2011) The phenotype of MDM2 auto-degradation after DNA damage is due to epitope masking by phosphorylation. Cell Cycle 10:1162-1166.
21. Chen L, Gilkes DM, Pan Y, Lane WS, Chen J (2005) ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage. EMBO J 24:3411-3422. (Pubitemid 41486779)
22. Kawai H, et al. (2003) DNA damage-induced MDMX degradation is mediated by MDM2. J Biol Chem 278:45946-45953. (Pubitemid 37432741)
23. Li C, Chen L, Chen J (2002) DNA damage induces MDMX nuclear translocation by p53-dependent and -independent mechanisms. Mol Cell Biol 22:7562-7571.
24. Jackson MW, Berberich SJ (2000) MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol 20:1001-1007. (Pubitemid 30044237)
25. Gu J, et al. (2002) Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 277:19251-19254. (Pubitemid 34967428)
26. Wang Y, et al. (2011) Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation. J Clin Invest 121:893-904.
27. Terzian T, et al. (2007) Haploinsufficiency of Mdm2 and Mdm4 in tumorigenesis and development. Mol Cell Biol 27:5479-5485. (Pubitemid 47124400)
28. Itahana K, et al. (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12:355-366. (Pubitemid 47539309)
29. Wang YV, Leblanc M, Wade M, Jochemsen AG, Wahl GM (2009) Increased radio-resistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases. Cancer Cell 16:33-43.
30. Rallapalli R, Strachan G, Cho B, Mercer WE, Hall DJ (1999) A novel MDMX transcript expressed in a variety of transformed cell lines encodes a truncated protein with potent p53 repressive activity. J Biol Chem 274:8299-8308.
31. Riemenschneider MJ, et al. (1999) Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification. Cancer Res 59:6091-6096. (Pubitemid 30035626)
32. Bartel F, et al. (2005) Significance of HDMX-S (or MDM4) mRNA splice variant overexpression and HDMX gene amplification on primary soft tissue sarcoma prognosis. Int J Cancer 117:469-475. (Pubitemid 41429571)
33. Xiong S, Van Pelt CS, Elizondo-Fraire AC, Fernandez-Garcia B, Lozano G (2007) Loss of Mdm4 results in p53-dependent dilated cardiomyopathy. Circulation 115:2925-2930. (Pubitemid 46912095)
34. Valentin-Vega YA, Barboza JA, Chau GP, El-Naggar AK, Lozano G (2007) High levels of the p53 inhibitor MDM4 in head and neck squamous carcinomas. Hum Pathol 38: 1553-1562. (Pubitemid 47418967)
35. Riemenschneider MJ, Knobbe CB, Reifenberger G (2003) Refined mapping of 1q32 amplicons in malignant gliomas confirms MDM4 as the main amplification target. Int J Cancer 104:752-757. (Pubitemid 36418513)
36. Laurie NA, et al. (2006) Inactivation of the p53 pathway in retinoblastoma. Nature 444:61-66. (Pubitemid 44684754)
37. Lewandoski M, Wassarman KM, Martin GR (1997) Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr Biol 7:148-151. (Pubitemid 27155624)
38. Post SM, et al. (2010) A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18:220-230.