MDM4 enhances p53 stability by promoting an active conformation of the protein upon DNA damage

Cell Cycle

Volumn 11, Issue 4, 2012, Pages 749-760

  Di Conza, Giusy ^a,b   Mancini, Francesca ^a,c   Buttarelli, Marianna ^a   Pontecorvi, Alfredo ^c   Trimarchi, Francesco ^b   Moretti, Fabiola ^a  

^a CNR   (Italy)

^b UNIVERSITY OF MESSINA   (Italy)

^c CATHOLIC UNIVERSITY   (Italy)

Author keywords

Conformation; MDM2; MDM4; MDMX; p53 stability; Stress response; Ubiquitin independent degradation

Indexed keywords

PROTEASOME; PROTEIN MDMX; PROTEIN P53; UBIQUITIN;

ANIMAL CELL; ARTICLE; CONFORMATIONAL TRANSITION; CONTROLLED STUDY; CYTOPLASM; DNA DAMAGE; GENETIC MODEL; MOLECULAR MECHANICS; MOUSE; NONHUMAN; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STABILITY; RNA INTERFERENCE; UBIQUITINATION;

EID: 84857490009     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.11.4.19208     Document Type: Article

References (52)

1. Hock A, Vousden KH. Regulation of the p53 pathway by ubiquitin and related proteins. Int J Biochem Cell Biol 2010; 42:1618-21; PMID:20601087; http://dx.doi.org/10.1016/j.biocel.2010.06.011.
2. Lee JT, Gu W. The multiple levels of regulation by p53 ubiquitination. Cell Death Differ 2010; 17:86-92; PMID:19543236; http://dx.doi.org/10.1038/cdd. 2009.77.
3. Marine JC, Lozano G. Mdm2-mediated ubiquitylation: p53 and beyond. Cell Death Differ 2010; 17:93-102; PMID:19498444; http://dx.doi.org/10.1038/cdd.2009. 68.
4. Okamoto K, Taya Y, Nakagama H. Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase. FEBS Lett 2009; 583:2710-4; PMID:19619542; http://dx.doi.org/10.1016/j.febslet.2009.07.021.
5. 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; 15:841-8; PMID:18219319; http://dx.doi.org/10.1038/sj.cdd.4402309.
6. Wang X, Wang J, Jiang X. MdmX protein is essential for Mdm2 protein-mediated p53 polyubiquitination. J Biol Chem 2011; 286:23725-34; PMID:21572037; http://dx.doi.org/10.1074/jbc.M110.213868.
7. Bell S, Klein C, Müller L, Hansen S, Buchner J. p53 contains large unstructured regions in its native state. J Mol Biol 2002; 322:917-27; PMID:12367518; http://dx.doi.org/10.1016/S0022-2836(02)00848-3.
8. Tsvetkov P, Reuven N, Prives C, Shaul Y. Susceptibility of p53 unstructured N terminus to 20 S proteasomal degradation programs the stress response. J Biol Chem 2009; 284:26234-42; PMID:19617345; http://dx.doi.org/10. 1074/jbc.M109.040493.
9. Kruse JP, Gu W. Modes of p53 regulation. Cell 2009; 137:609-22; PMID:19450511; http://dx.doi.org/10.1016/j.cell.2009.04.050.
10. Meek DW. Tumour suppression by p53: a role for the DNA damage response? Nat Rev Cancer 2009; 9:714-23; PMID:19730431.
11. Miliani de Marval PL, Zhang Y. The RP-Mdm2-p53 pathway and tumorigenesis. Oncotarget 2011; 2:234-8; PMID:21406728.
12. Inuzuka H, Fukushima H, Shaik S, Wei W. Novel insights into the molecular mechanisms governing Mdm2 ubiquitination and destruction. Oncotarget 2010; 1:685-90; PMID:21317463.
13. Asher G, Lotem J, Cohen B, Sachs L, Shaul Y. Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1. Proc Natl Acad Sci USA 2001; 98:1188-93; PMID:11158615; http://dx.doi.org/10.1073/pnas.021558898.
14. Asher G, Lotem J, Kama R, Sachs L, Shaul Y. NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci USA 2002; 99:3099-104; PMID:11867746; http://dx.doi.org/10.1073/pnas.052706799.
15. Asher G, Lotem J, Sachs L, Kahana C, Shaul Y. Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci USA 2002; 99:13125-30; PMID:12232053; http://dx.doi.org/10.1073/pnas. 202480499.
16. Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA, et al. Interaction of human NAD(P) H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems. J Biol Chem 2003; 278:10368-73; PMID:12529318; http://dx.doi.org/10.1074/jbc.M211981200.
17. Asher G, Tsvetkov P, Kahana C, Shaul Y. A mechanism of ubiquitin-independent proteasomal degradation of the tumor suppressors p53 and p73. Genes Dev 2005; 19:316-21; PMID:15687255; http://dx.doi.org/10.1101/gad. 319905.
18. Gong X, Kole L, Iskander K, Jaiswal AK. NRH:quinone oxidoreductase 2 and NAD(P)H:quinone oxidoreductase 1 protect tumor suppressor p53 against 20s proteasomal degradation leading to stabilization and activation of p53. Cancer Res 2007; 67:5380-8; PMID:17545619; http://dx.doi.org/10.1158/0008-5472.CAN-07- 0323.
19. Jackson MW, Berberich SJ. MdmX protects p53 from Mdm2-mediated degradation. Mol Cell Biol 2000; 20:1001-7; PMID:10629057; http://dx.doi.org/10. 1128/MCB.20.3.1001-7.2000.
20. Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP, et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2001; 2:1029-34; PMID:11606419; http://dx.doi.org/10.1093/embo-reports/kve227.
21. Gu J, Kawai H, Nie L, Kitao H, Wiederschain D, Jochemsen AG, et al. Mutual dependence of MDM2 and MDMX in their functional inactivation of p53. J Biol Chem 2002; 277:19251-4; PMID:11953423; http://dx.doi.org/10.1074/jbc. C200150200.
22. Migliorini D, Danovi D, Colombo E, Carbone R, Pelicci PG, Marine JC. Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation. J Biol Chem 2002; 277:7318-23; PMID:11744695; http://dx.doi.org/10.1074/jbc.M108795200.
23. Mancini F, Gentiletti F, D'Angelo M, Giglio S, Nanni S, D'Angelo C, et al. MDM4 (MDMX) overexpression enhances stabilization of stress-induced p53 and promotes apoptosis. J Biol Chem 2004; 279:8169-80; PMID:14660608; http://dx.doi.org/10.1074/jbc.M311793200.
24. Lenos K, de Lange J, Teunisse AF, Lodder K, Verlaande Vries M, Wiercinska E, et al. Oncogenic functions of hMDMX in in vitro transformation of primary human fibroblasts and embryonic retinoblasts. Mol Cancer 2011; 10:111; PMID:21910853; http://dx.doi.org/10.1186/1476-4598-10-111.
25. Barboza JA, Iwakuma T, Terzian T, El-Naggar AK, Lozano G. Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol Cancer Res 2008; 6:947-54; PMID:18567799; http://dx.doi.org/10.1158/1541-7786.MCR-07-2079.
26. Li Z, Day CP, Yang JY, Tsai WB, Lozano G, Shih HM, et al. Adenoviral E1A targets Mdm4 to stabilize tumor suppressor p53. Cancer Res 2004; 64:9080-5; http://dx.doi.org/10.1158/0008-5472.CAN-04-2419; PMID:15604276.
27. Francoz S, Froment P, Bogaerts S, De Clercq S, Maetens M, Doumont G, et al. Mdm4 and Mdm2 cooperate to inhibit p53 activity in proliferating and quiescent cells in vivo. Proc Natl Acad Sci USA 2006; 103:3232-7; PMID:16492744; http://dx.doi.org/10.1073/pnas.0508476103.
28. Xiong S, Pant V, Suh YA, Van Pelt CS, Wang Y, Valentin-Vega YA, et al. Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res 2010; 70:7148-54; PMID:20736370; http://dx.doi.org/10.1158/ 0008-5472.CAN-10-1457.
29. Li B, Dou QP. Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. Proc Natl Acad Sci USA 2000; 97:3850-5; PMID:10725400; http://dx.doi.org/10.1073/pnas.070047997.
30. Salvat C, Acquaviva C, Scheffner M, Robbins I, Piechaczyk M, Jariel-Encontre I. Molecular characterization of the thermosensitive E1 ubiquitin-activating enzyme cell mutant A31N-ts20. Requirements upon different levels of E1 for the ubiquitination/degradation of the various protein substrates in vivo. Eur J Biochem 2000; 267:3712-22; PMID:10848989; http://dx.doi.org/10.1046/j.1432-327.2000.01404.x.
31. Mancini F, Di Conza G, Pellegrino M, Rinaldo C, Prodosmo A, Giglio S, et al. MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. EMBO J 2009; 28:1926-39; PMID:19521340; http://dx.doi.org/10.1038/emboj.2009.154.
32. Mancini F, Di Conza G, Monti O, Macchiarulo A, Pellicciari R, Pontecorvi A, et al. Puzzling over MDM4-p53 network. Int J Biochem Cell Biol 2010; 42:1080-3; PMID:20417304; http://dx.doi.org/10.1016/j.biocel.2010.04.010.
33. Lowe SW, Ruley HE, Jacks T, Housman DE. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 1993; 74:957-67; PMID:8402885; http://dx.doi.org/10.1016/0092-8674(93)90719-7.
34. Soule HD, Maloney TM, Wolman SR, Peterson WD Jr, Brenz R, McGrath CM, et al. Isolation and characterization of a spontaneously immortalized human breast epithelial cell line, MCF-10. Cancer Res 1990; 50:6075-86; PMID:1975513.
35. Kulikov R, Letienne J, Kaur M, Grossman SR, Arts J, Blattner C. Mdm2 facilitates the association of p53 with the proteasome. Proc Natl Acad Sci USA 2010; 107:10038-43; PMID:20479273; http://dx.doi.org/10.1073/pnas.0911716107.
36. Mayr GA, Reed M, Wang P, Wang Y, Schweds JF, Tegtmeyer P. Serine phosphorylation in the NH2 terminus of p53 facilitates transactivation. Cancer Res 1995; 55:2410-7; PMID:7757994.
37. Marchenko ND, Hanel W, Li D, Becker K, Reich N, Moll UM. Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ 2010; 17:255-67; PMID:19927155; http://dx.doi.org/10. 1038/cdd.2009.173.
38. Marine JC. p53 stabilization: the importance of nuclear import. Cell Death Differ 2010; 17:191-2; PMID:20062067; http://dx.doi.org/10.1038/cdd.2009. 183.
39. Mancini F, Moretti F. Mitochondrial MDM4 (MDMX): an unpredicted role in the p53-mediated intrinsic apoptotic pathway. Cell Cycle 2009; 8:3854-9; PMID:19887911; http://dx.doi.org/10.4161/cc.8.23.10089.
40. Sasaki M, Nie L, Maki CG. MDM2 binding induces a conformational change in p53 that is opposed by heat-shock protein 90 and precedes p53 proteasomal degradation. J Biol Chem 2007; 282:14626-34; PMID:17363365; http://dx.doi.org/ 10.1074/jbc.M610514200.
41. Carotti A, Macchiarulo A, Giacchè N, Pellicciari R. Targeting the conformational transitions of MDM2 and MDMX: insights into key residues affecting p53 recognition. Proteins 2009; 77:524-35; PMID:19507240; http://dx.doi.org/10.1002/prot.22464.
42. Popowicz GM, Czarna A, Holak TA. Structure of the human Mdmx protein bound to the p53 tumor suppressor transactivation domain. Cell Cycle 2008; 7:2441-3; PMID:18677113.
43. Popowicz GM, Czarna A, Rothweiler U, Szwagierczak A, Krajewski M, Weber L, et al. Molecular basis for the inhibition of p53 by Mdmx. Cell Cycle 2007; 6:2386-92; PMID:17938582; http://dx.doi.org/10.4161/cc.6.19.4740.
44. Zdzalik M, Pustelny K, Kedracka-Krok S, Huben K, Pecak A, Wladyka B, et al. Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73. Cell Cycle 2010; 9:4584-91; PMID:21088494; http://dx.doi.org/10.4161/ cc.9.22.13871.
45. Azmi AS, Banerjee S, Ali S, Wang Z, Bao B, Beck FW, et al. Network modeling of MDM2 inhibitor-oxaliplatin combination reveals biological synergy in wt-p53 solid tumors. Oncotarget 2011; 2:378-92; PMID:21623005.
46. Jin Y, Dai MS, Lu SZ, Xu Y, Luo Z, Zhao Y, et al. 14-3-3gamma binds to MDMX that is phosphorylated by UV-activated Chk1, resulting in p53 activation. EMBO J 2006; 25:1207-18; PMID:16511572; http://dx.doi.org/10.1038/sj.emboj. 7601010.
47. Wang YV, Leblanc M, Wade M, Jochemsen AG, Wahl GM. Increased radioresistance and accelerated B cell lymphomas in mice with Mdmx mutations that prevent modifications by DNA-damage-activated kinases. Cancer Cell 2009; 16:33-43; PMID:19573810; http://dx.doi.org/10.1016/j.ccr.2009.05.008.
48. Wang YV, Wade M, Wahl GM. Guarding the guardian: Mdmx plays important roles in setting p53 basal activity and determining biological responses in vivo. Cell Cycle 2009; 8:3443-4; PMID:19838055; http://dx.doi.org/10.4161/cc.8. 21.9744.
49. Ménendez S, Goh AM, Camus S, Ng KW, Kua N, Badal V, et al. MDM4 downregulates p53 transcriptional activity and response to stress during differentiation. Cell Cycle 2011; 10:1100-8; PMID:21422812; http://dx.doi.org/ 10.4161/cc.10.7.15090.
50. Li B, Cheng Q, Li Z, Chen J. p53 inactivation by MDM2 and MDMX negative feedback loops in testicular germ cell tumors. Cell Cycle 2010; 9:1411-20; PMID:20372076; http://dx.doi.org/10.4161/cc.9.7.11255.
51. Kim S, Aladjem MI, McFadden GB, Kohn KW. Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage. PLoS Comput Biol 2010; 6:1000665; PMID:20174603; http://dx.doi.org/10.1371/journal.pcbi.1000665.
52. Prodosmo A, Giglio S, Moretti S, Mancini F, Barbi F, Avenia N, et al. Analysis of human MDM4 variants in papillary thyroid carcinomas reveals new potential markers of cancer properties. J Mol Med (Berl) 2008; 86:585-96; PMID:18335186; http://dx.doi.org/10.1007/s00109-008-0322-6.