Murine double minute 2, a potential p53-independent regulator of liver cancer metastasis

Abstract

Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the mechanisms underlying HCC progression remain unclear. Unlike other cancers, systematic chemotherapy is not effective for HCC patients, while surgical resection and liver transplantation are the most viable treatment options. Thus, identifying factors or pathways that suppress HCC progression would be crucial for advancing treatment strategies for HCC. The murine double minute 2 (MDM2)-p53 pathway is impaired in most of the cancer types, including HCC, and MDM2 is overexpressed in approximately 30% of HCC. Overexpression of MDM2 is reported to be well correlated with metastasis, drug resistance, and poor prognosis of multiple cancer types, including HCC. Importantly, these correlations are observed even when p53 is mutated. Indeed, p53-independent functions of overexpressed MDM2 in cancer progression have been suitably demonstrated. In this review article, we summarize potential effectors of MDM2 that promote or suppress cancer metastasis and specifically discuss the p53-independent roles of MDM2 in liver cancer metastasis from clinical as well as biological perspectives.

Keywords

Murine double minute 2 / metastasis / effectors / hepatocellular carcinoma / p53 independent

References

[1] Torre LA,Siegel RL,Lortet-Tieulent J.Global cancer statistics, 2012..CA Cancer J Clin2015;65:87-108

[2] Dhanasekaran R,Cabrera R.Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics..Hepat Med2012;4:19-37 PMCID:PMC3846594

[3] Bialecki ES.Diagnosis of hepatocellular carcinoma..HPB (Oxford)2005;7:26-34 PMCID:PMC2023919

[4] Zhang HY,Xie CH.Long-term survival of patients with hepatocellular carcinoma with pulmonary and adrenal metastasis: A case report..Exp Ther Med2012;3:699-702 PMCID:PMC3438783

[5] Davis GL,Meler JD,Walberg MW,Berger BD,Goldstein RM.Hepatocellular carcinoma: management of an increasingly common problem..Proc (Bayl Univ Med Cent)2008;21:266-80

[6] Meng X,Dong J.MDM2-p53 pathway in hepatocellular carcinoma..Cancer Res2014;74:7161-7 PMCID:PMC4504428

[7] Valastyan S.Tumor metastasis: molecular insights and evolving paradigms..Cell2011;147:275-92 PMCID:PMC3261217

[8] van Zijl F,Petz M,Kornauth C,Machat G,Huber H.Epithelial-mesenchymal transition in hepatocellular carcinoma..Future Oncol2009;5:1169-79 PMCID:PMC2963061

[9] Cahilly-Snyder L,Francke U.Molecular analysis and chromosomal mapping of amplified genes isolated from a transformed mouse 3T3 cell line..Somat Cell Mol Genet1987;13:235-44

[10] Fakharzadeh SS,George DL.Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line..EMBO J1991;10:1565-9 PMCID:PMC452821

[11] Iwakuma T.MDM2, an introduction..Mol Cancer Res2003;1:993-1000

[12] Onel K.MDM2 and prognosis..Mol Cancer Res2004;2:1-8

[13] Jones SN,Vogel H,Bradley A.Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis..Proc Natl Acad Sci U S A1998;95:15608-12 PMCID:PMC28091

[14] Lundgren K,McNeill YB,Spencer B,Lozano G,Finlay CA.Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53..Genes Dev1997;11:714-25

[15] Bouska A,Plaza S.Mdm2 promotes genetic instability and transformation independent of p53..Mol Cell Biol2008;28:4862-74 PMCID:PMC2493369

[16] Alt JRJR,Fernandez MR,Xiao H.Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair..J Biol Chem2005;280:18771-81

[17] Jin Y,Zeng SX,Lu H.MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation..Embo J2003;22:6365-77 PMCID:PMC291841

[18] Zhang Z,Li M,Chen X.MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53..J Biol Chem2004;279:16000-6

[19] Martin K,Hagemeier C,La Thangue NB.Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein..Nature1995;375:691-4

[20] Sdek P,Zheng H,Tang X,Xiao ZX.The central acidic domain of MDM2 is critical in inhibition of retinoblastoma-mediated suppression of E2F and cell growth..J Biol Chem2004;279:53317-22

[21] Gu L,Zhou M.MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia..Blood2002;99:3367-75

[22] Johnson-Pais T,Thayer MJ.pRB induces Sp1 activity by relieving inhibition mediated by MDM2..Proc Natl Acad Sci U S A2001;98:2211-6 PMCID:PMC30117

[23] Riley MF.The many faces of MDM2 binding partners..Genes Cancer2012;3:226-39 PMCID:PMC3494375

[24] Zhu MH,Zhu Z,Zhang SM.[Determination of expression of eight p53-related genes in hepatocellular carcinoma with tissue microarrays]..Ai Zheng2003;22:680-5

[25] Qiu SJ,Wu ZQ,Liu YK.The expression of the mdm2 gene may be related to the aberration of the p53 gene in human hepatocellular carcinoma..J Cancer Res Clin Oncol1998;124:253-8

[26] Zhou XD.Recurrence and metastasis of hepatocellular carcinoma: progress and prospects..Hepatobiliary Pancreat Dis Int2002;1:35-41

[27] Qiu S,Wu Z.The expression of mdm2 gene related to the invasiveness of human hepatocellular carcinoma..Zhonghua Zhong Liu Za Zhi1997;19:256-9

[28] Wang GL,Rue EA.Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension..Proc Natl Acad Sci U S A1995;92:5510-4 PMCID:PMC41725

[29] Luo D,Wu J,Wu J.The role of hypoxia inducible factor-1 in hepatocellular carcinoma..Biomed Res Int2014;2014:409272 PMCID:PMC4101982

[30] Zhang L,Li X,Jiang Y,Liu J,Zhu J,Dong J.Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma..BMC Cancer2013;13:108 PMCID:PMC3614870

[31] Zhong H,Laughner E,Hilton DA,Buechler P,Semenza GL.Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases..Cancer Res1999;59:5830-5

[32] Tanaka H,Hashimoto N,Tamakawa S,Tokusashi Y,Yaginuma Y.Hypoxia-independent overexpression of hypoxia-inducible factor 1alpha as an early change in mouse hepatocarcinogenesis..Cancer Res2006;66:11263-70

[33] Zheng SS,Yin X.Prognostic significance of HIF-1alpha expression in hepatocellular carcinoma: a meta-analysis..PLoS One2013;8:e65753 PMCID:PMC3683060

[34] Dai CX,Qiu SJ,Cai MY,Zhou J,Fan J.Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery..BMC Cancer2009;9:418 PMCID:PMC2797816

[35] Yang SL,Jiang JX,He QJ.The correlation of expression levels of HIF-1alpha and HIF-2alpha in hepatocellular carcinoma with capsular invasion, portal vein tumor thrombi and patients' clinical outcome..Jpn J Clin Oncol2014;44:159-67

[36] Chen D,Luo J.Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function..J Biol Chem2003;278:13595-8

[37] Nieminen AL,Schneider EA,Agani FH.Mdm2 and HIF-1alpha interaction in tumor cells during hypoxia..J Cell Physiol2005;204:364-9

[38] Joshi S,Durden DL.MDM2 regulates hypoxic hypoxia-inducible factor 1alpha stability in an E3 ligase, proteasome, and PTEN-phosphatidylinositol 3-kinase-AKT-dependent manner..J Biol Chem2014;289:22785-97 PMCID:PMC4132784

[39] Ravi R,Bhujwalla ZM,Artemov D,Dillehay LE,Semenza GL.Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha..Genes Dev2000;14:34-44 PMCID:PMC316350

[40] Alves CC,Hoefler H.Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers..Front Biosci (Landmark Ed)2009;14:3035-50

[41] Zhao X,Sun D,Che N,Dong X,Liu Y.Slug promotes hepatocellular cancer cell progression by increasing sox2 and nanog expression..Oncol Rep2015;33:149-56

[42] Sun Y,Sun N,Yang SS.Slug overexpression induces stemness and promotes hepatocellular carcinoma cell invasion and metastasis..Oncol Lett2014;7:1936-40 PMCID:PMC4049749

[43] Sun D,Liu T,Che N,Dong X,Li R,Chi J.Slug promoted vasculogenic mimicry in hepatocellular carcinoma..J Cell Mol Med2013;17:1038-47 PMCID:PMC3780534

[44] Jung CH,Park JK,Moon SK,Um HD.Mdm2 increases cellular invasiveness by binding to and stabilizing the Slug mRNA..Cancer Lett2013;335:270-7

[45] Sternlicht MD.How matrix metalloproteinases regulate cell behavior..Annu Rev Cell Dev Biol2001;17:463-516 PMCID:PMC2792593

[46] Arii S,Harada T,Ishigami S,Mizumoto M,Imamura M.Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential..Hepatology1996;24:316-22

[47] Sakamoto Y,Mori M,Imamura H,Shiraishi T,Mori M,Makuuchi M.Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma..Int J Oncol2000;17:237-43

[48] Zhao XL,Che N,Zhao N,Gu Q,Sun BC.Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1..J Cell Mol Med2011;15:691-700 PMCID:PMC3922390

[49] Yang P,He J,Yu L,Hu Y,Chen Z.Overexpression of EphA2, MMP-9, and MVD-CD34 in hepatocellular carcinoma: Implications for tumor progression and prognosis..Hepatol Res2009;39:1169-77

[50] Zhang DH,Liu DJ,Zhao JZ.Expression and significance of MMP-9 and MDM2 in the oncogenesis of lung cancer in rats..Asian Pac J Trop Med2014;7:585-8

[51] Chen X,Yang D,Yan C,Yin Y.MDM2 Promotes Invasion and Metastasis in Invasive Ductal Breast Carcinoma by Inducing Matrix Metalloproteinase-9..PLoS One2013;8:e78794 PMCID:PMC3827260

[52] Shi W,Chen Z,Gao H,Lin J,Luo J.RNA interference against MDM2 suppresses tumor growth and metastasis in pancreatic carcinoma SW1990HM cells..Mol Cell Biochem2014;387:1-8

[53] Campos AR,White K.Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects. A developmental-genetic analysis..J Neurogenet1985;2:197-218

[54] Ma WJ,Campbell C,Furneaux H.Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein..J Biol Chem1996;271:8144-51

[55] Srikantan S.HuR function in disease..Front Biosci (Landmark Ed)2012;17:189-205

[56] Dixon DA,King PH,McIntyre TM,Prescott SM.Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells..J Clin Invest2001;108:1657-65 PMCID:PMC200983

[57] Lopez de Silanes I,Gorospe M.HuR: post-transcriptional paths to malignancy..RNA Biol2005;2:11-3

[58] Zhu H,Mathur R,Khashab T,Ao X,Sabichi AL,Rashid A.HuR Suppresses Fas Expression and Correlates with Patient Outcome in Liver Cancer..Mol Cancer Res2015;13:809-18

[59] Vazquez-Chantada M,Embade N,Varela-Rey M,Luka Z,Anglim PP,Caballería J,Gorospe M,Mato JM.HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis..Gastroenterology2010;138:1943-53 PMCID:PMC2860011

[60] Embade N,Varela-Rey M,Sini M,Woodhoo A,Rodríguez-Iruretagoyena B,de la Hoz AB,Xirodimas DP,Lu SC,Martínez-Chantar ML.Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation..Hepatology2012;55:1237-48 PMCID:PMC3298572

[61] Gumbiner BM.Regulation of cadherin-mediated adhesion in morphogenesis..Nat Rev Mol Cell Biol2005;6:622-34

[62] Halbleib JM.Cadherins in development: cell adhesion, sorting, and tissue morphogenesis..Genes Dev2006;20:3199-214

[63] Singhai R,Jaiswal SR,Tayade MB.E-Cadherin as a diagnostic biomarker in breast cancer..N Am J Med Sci2011;3:227-33 PMCID:PMC3337742

[64] Oka H,Kobayashi K,Tamura S,Doki Y,Matsuyoshi N,Takeichi M.Immunohistochemical evaluation of E-cadherin adhesion molecule expression in human gastric cancer..Virchows Arch A Pathol Anat Histopathol1992;421:149-56

[65] Bremnes RM,Hirsch FR.The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis..Lung Cancer2002;36:115-24

[66] Dorudi S,Poulsom R,Hart IR.E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study..Am J Pathol1993;142:981-6 PMCID:PMC1886882

[67] von Burstin J,Paul MC,Brandl M,von Werder A,Mages J,Schnieke A,Schneider G.E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex..Gastroenterology2009;137:361-71, 71 e1-5

[68] Asayama Y,Aishima Si S,Masuda K.The mode of tumour progression in combined hepatocellular carcinoma and cholangiocarcinoma: an immunohistochemical analysis of E-cadherin, alpha-catenin and beta-catenin..Liver2002;22:43-50

[69] Chen J,Ma R,Liang X.Prognostic significance of e-cadherin expression in hepatocellular carcinoma: a meta-analysis..PLoS One2014;9:e103952 PMCID:PMC4122395

[70] Gao ZH,Liu WH,Farris PD.Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma..Mod Pathol2006;19:533-40

[71] Schneider MR,Grill J,Krebs S,Bauersachs S,Longerich T,Brandl L,Herbst A.Evidence for a role of E-cadherin in suppressing liver carcinogenesis in mice and men..Carcinogenesis2014;35:1855-62

[72] Yang JY,Xia W,Ali-Seyed M,Broglio K,Hung MC.MDM2 promotes cell motility and invasiveness by regulating E-cadherin degradation..Mol Cell Biol2006;26:7269-82 PMCID:PMC1592879

[73] Hartsough MT.Nm23/nucleoside diphosphate kinase in human cancers..J Bioenerg Biomembr2000;32:301-8

[74] Thakur RK,Kumar A,Pal K,Saha D,Basundra R,Halder R,Baral A,Baldi A,Lorenzon L,Kumar P,Mukhopadhyay D.Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin..Nucleic Acids Res2014;42:11589-600 PMCID:PMC4191424

[75] Miyazaki H,Ishijima Y,Iimura T,Hirayama R,Amagasa T.Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture..Clin Cancer Res1999;5:4301-7

[76] Thakur RK,Kumar P.Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types..Naunyn Schmiedebergs Arch Pharmacol2011;384:397-406

[77] Lee MJ,Li H,Leem SH,Kim IH.Pro-oncogenic potential of NM23-H2 in hepatocellular carcinoma..Exp Mol Med2012;44:214-24 PMCID:PMC3317485

[78] Iizuka N,Noma T,Hirose K.NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma..Cancer Res1995;55:652-7

[79] Polanski R,Nield PC,Park BK,Devling T,Rubbi CP,Boyd MT.MDM2 interacts with NME2 (non-metastatic cells 2, protein) and suppresses the ability of NME2 to negatively regulate cell motility..Carcinogenesis2011;32:1133-42

[80] Yang A,Wang Y,Fleming MD,Andrews NC,McKeon F.p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities..Mol Cell1998;2:305-16

[81] Adorno M,Montagner M,Wong C,Solari A,Rondina MB,Parenti AR,Bicciato S,Piccolo S.A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis..Cell2009;137:87-98

[82] Gu X,Boldrup L.p63 contributes to cell invasion and migration in squamous cell carcinoma of the head and neck..Cancer Lett2008;263:26-34

[83] Melino G.p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53..Cell Death Differ2011;18:1487-99 PMCID:PMC3178431

[84] Tucci P,Grespi F,Terrinoni A,Muller PA,Kehrloesser S,Giaccone G,Takahashi N,Knight RA,Melino G.Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer..Proc Natl Acad Sci U S A2012;109:15312-7 PMCID:PMC3458363

[85] Park BJ,Kim JI,Lee CH,Park JH.Frequent alteration of p63 expression in human primary bladder carcinomas..Cancer Res2000;60:3370-4

[86] Spiesbach K,Mossner J.TAp63gamma can substitute for p53 in inducing expression of the maspin tumor suppressor..Int J Cancer2005;114:555-62

[87] Hara T,Yamamoto S,Kise Y,Chino O,Takazawa K,Inokuchi S.Ubiquitous p63 expression in human esophageal squamous cell carcinoma..Int J Mol Med2004;14:169-73

[88] Inoue K.Alterations of p63 and p73 in human cancers..Subcell Biochem2014;85:17-40 PMCID:PMC5356026

[89] Flores ER,Miller JB,Bronson R,Yang A,Jacks T.Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family..Cancer Cell2005;7:363-73

[90] Iwakuma T,Flores ER.Li-Fraumeni syndrome: a p53 family affair..Cell Cycle2005;4:865-7

[91] Zdzalik M,Kedracka-Krok S,Pecak A,Jankowski S,Potempa J.Interaction of regulators Mdm2 and Mdmx with transcription factors p53, p63 and p73..Cell Cycle2010;9:4584-91

[92] Kadakia M,Berberich SJ.Regulation of p63 function by Mdm2 and MdmX..DNA Cell Biol2001;20:321-30

[93] Stindt MH,Ludwig RL,Dotsch V.Functional interplay between MDM2, p63/p73 and mutant p53..Oncogene2015;34:4300-10 PMCID:PMC4351904

[94] Calabro V,Parisi T,Calogero RA.The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63..J Biol Chem2002;277:2674-81

[95] Lam EW,Gomes AR.Forkhead box proteins: tuning forks for transcriptional harmony..Nat Rev Cancer2013;13:482-95

[96] Xu D,Chang Y,Jiang X,Lin J.Inhibition of miR-96 expression reduces cell proliferation and clonogenicity of HepG2 hepatoma cells..Oncol Rep2013;29:653-61

[97] Arden KC.Multiple roles of FOXO transcription factors in mammalian cells point to multiple roles in cancer..Exp Gerontol2006;41:709-17

[98] Yamaguchi F,Akram H,Dong Y,Tokuda M.FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801..BMC Cancer2013;13:468 PMCID:PMC3852080

[99] Zou Y,Cheng CJ,Chung YM,Lin SH.Forkhead box transcription factor FOXO3a suppresses estrogen-dependent breast cancer cell proliferation and tumorigenesis..Breast Cancer Res2008;10:R21 PMCID:PMC2374977

[100] Blake DC., Mikse OR, Freeman WM, Herzog CR. FOXO3a elicits a pro-apoptotic transcription program and cellular response to human lung carcinogen nicotine-derived nitrosaminoketone (NNK)..Lung Cancer2010;67:37-47

[101] Ni D,Li HZ,Li XT,Ai Q,Song EL,Fan Y.Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma..Clin Cancer Res2014;20:1779-90

[102] Cheng CW,Hsieh YH,Chang CW,Hu LY,Shen CY.Foxo3a-mediated overexpression of microRNA-622 suppresses tumor metastasis by repressing hypoxia-inducible factor-1alpha in erk-responsive of lung cancer.Oncotarget2015;

[103] Liu H,Wang H,Deng M,Bu X,Du J.FOXO3a modulates WNT/beta-catenin signaling and suppresses epithelial-to-mesenchymal transition in prostate cancer cells..Cell Signal2015;27:510-8

[104] Shiota M,Yokomizo A,Tada Y,Uchiumi T,Oda Y,Tatsugami K.Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation..Clin Cancer Res2010;16:5654-63

[105] Su B,Baranowski C,Wang J,Ko HK.A genome-wide RNAi screen identifies FOXO4 as a metastasis-suppressor through counteracting PI3K/AKT signal pathway in prostate cancer..PLoS One2014;9:e101411 PMCID:PMC4077825

[106] Xu MM,Liu J,Huang H,Liu JH.Low expression of the FoxO4 gene may contribute to the phenomenon of EMT in non-small cell lung cancer..Asian Pac J Cancer Prev2014;15:4013-8

[107] Xie C,Wu JH,Yun JP,Xie DY,Yuan YF,Gao ZL.Upregulator of cell proliferation predicts poor prognosis in hepatocellular carcinoma and contributes to hepatocarcinogenesis by downregulating FOXO3a..PLoS One2012;7:e40607 PMCID:PMC3398045

[108] Lu M,Xue W,Wang Y,Ke Q,Liu Y,Cui X,Shen A.The expression and prognosis of FOXO3a and Skp2 in human hepatocellular carcinoma..Pathol Oncol Res2009;15:679-87

[109] Carbajo-Pescador S,Garcia-Palomo A.FoxO proteins: regulation and molecular targets in liver cancer..Curr Med Chem2014;21:1231-46

[110] Yang JY,Xia W,Ding Q,Lang JY,Chang CJ,Huang H,Lee DF,Lien HC,Chang KJ,Tsai FJ,Sahin AA,Mills GB,Hortobagyi GN.ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation..Nat Cell Biol2008;10:138-48 PMCID:PMC2376808

[111] Fu W,Chen L,Zhang M,Nawaz Z,Wang H,Shen Z,Zhang X,Zhang Y,Chen J.MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation..J Biol Chem2009;284:13987-4000 PMCID:PMC2682847

[112] Brenkman AB,van den Broek NJ,Burgering BM.Mdm2 induces mono-ubiquitination of FOXO4..PLoS One2008;3:e2819 PMCID:PMC2475507

[113] Boyd MT,Haines DS.A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2..J Biol Chem2000;275:31883-90

[114] Agarwal N,Adhikari AS,Cui Y.MTBP plays a crucial role in mitotic progression and chromosome segregation..Cell Death Differ2011;18:1208-19 PMCID:PMC3131950

[115] Agarwal N,Iyer SV,Welch DR.MTBP suppresses cell migration and filopodia formation by inhibiting ACTN4..Oncogene2013;32:462-70 PMCID:PMC3742333

[116] Bi Q,Fan R,Welch DR,Ding J.MTBP inhibits migration and metastasis of hepatocellular carcinoma..Clin Exp Metastasis2015;32:301-11 PMCID:PMC4510982

[117] Iwakuma T,Van Pelt CS,Terzian T,Chau GP,Eischen CM.Mtbp haploinsufficiency in mice increases tumor metastasis..Oncogene2008;27:1813-20

[118] Vlatkovic N,Devling T,Gore DM,Dodson A,Helliwell TR,Boyd MT.Loss of MTBP expression is associated with reduced survival in a biomarker-defined subset of patients with squamous cell carcinoma of the head and neck..Cancer2011;117:2939-50

[119] Odvody J,Arrate MP,Wang S,Lozano G,Haines DS.A deficiency in Mdm2 binding protein inhibits Myc-induced B-cell proliferation and lymphomagenesis..Oncogene2010;29:3287-96 PMCID:PMC2880662

[120] Grieb BC,Eischen CM.MTBP is Over-expressed in Triple Negative Breast Cancer and Contributes to its Growth and Survival..Mol Cancer Res2014;12:1216-24 PMCID:PMC4163510

[121] Grieb BC,Arrate MP,Beauparlant SL,Xiao H.Oncogenic protein MTBP interacts with MYC to promote tumorigenesis..Cancer Res2014;74:3591-602 PMCID:PMC4079748

[122] Lu S,Wei H,Li L.MTBP Promotes the Invasion and Metastasis of Hepatocellular Carcinoma by Enhancing the MDM2-Mediated Degradation of E-Cadherin..Dig Dis Sci2015;60:3681-90

[123] Aleixo PB,Menezes IC,Oliveira AM.Can MDM2 and CDK4 make the diagnosis of well differentiated/dedifferentiated liposarcoma? An immunohistochemical study on 129 soft tissue tumours..J Clin Pathol2009;62:1127-35

[124] Reifenberger G,Ichimura K,Collins VP.Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations..Cancer Res1993;53:2736-9

[125] Bond GL,Bond EE,Lutzker SG,Bargonetti J,Taubert H,Onel K,Hwang SJ,Lozano G.A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans..Cell2004;119:591-602

[126] Weber JD,Roussel MF,Bar-Sagi D.Nucleolar Arf sequesters Mdm2 and activates p53..Nat Cell Biol1999;1:20-6

[127] Malmlof M,Hogberg J.MEK-ERK-mediated phosphorylation of Mdm2 at Ser-166 in hepatocytes. Mdm2 is activated in response to inhibited Akt signaling..J Biol Chem2007;282:2288-96

[128] Capoulade C,Lefrere I,Feunteun J,Wiels J.Overexpression of MDM2, due to enhanced translation, results in inactivation of wild-type p53 in Burkitt's lymphoma cells..Oncogene1998;16:1603-10

[129] Zhao Y,Hu W.The regulation of MDM2 oncogene and its impact on human cancers..Acta Biochim Biophys Sin (Shanghai)2014;46:180-9 PMCID:PMC3932834