Abstract
Many types of human cancers overexpress MDM2 protein. A common characteristic among these cancers is an associated increase in mdm2 splice variants. Provided here is a comprehensive list, based on a literature review, of over 70 mdm2 variants. These variants are grouped according to in-frame versus out-of-frame status and their potential (or ability) to be translated into isoform proteins. We describe the putative functions for these mdm2 splice variant mRNAs, as well as the mechanistic drivers associated with increased mdm2 transcription and splicing. The paradoxical signal transduction functions of the most commonly studied variants mdm2-a,-b and -c are addressed for their outcomes in the presence and absence of wild-type p53. These outcomes vary from tumor promotion to growth arrest. Finally, we present issues in the detection of endogenous MDM2 protein and how many of the antibodies commonly used to detect MDM2 do not present a full picture of the cellular representation of the isoform proteins. This review provides a focusing lens for individuals interested in learning about the complexities of mdm2 mRNAs and their protein isoforms as well as the roles MDM2 isoforms may play in cancer progression.
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References
Jeyaraj S, O’Brien DM, Chandler DS (2009) MDM2 and MDM4 splicing: an integral part of the cancer spliceome. Front Biosci 14:2647–2656, doi:3402 [pii]
Bartel F, Taubert H, Harris LC (2002) Alternative and aberrant splicing of MDM2 mRNA in human cancer. Cancer Cell 2(1):9–15
Tilgner H, Knowles DG, Johnson R, Davis CA, Chakrabortty S, Djebali S, Curado J, Snyder M, Gingeras TR, Guigo R (2012) Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs. Genome Res 22(9):1616–1625. doi:10.1101/gr.134445.111
Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kelllis M, Kheradpour P, Lassman T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Bernstein BE, Green ED, Gunter C, Snyder M, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Good PJ, Feingold EA, Crawford GE, Dekker J, Elinitski L, Farnham PJ, Giddings MC, Gingeras TR, Guigo R, Hubbard TJ, Kellis M, Kent WJ, Lieb JD, Margulies EH, Myers RM, Starnatoyannopoulos JA, Tennebaum SA, Weng Z, White KP, Wold B, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Mikkelsen TS, Gillespie S, Goren A, Ram O, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Eaton ML, Dobin A, Lassmann T, Tanzer A, Lagarde J, Lin W, Xue C, Williams BA, Zaleski C, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Batut P, Bell I, Bell K, Chakrabortty S, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Li G, Luo OJ, Park E, Preall JB, Presaud K, Ribeca P, Robyr D, Ruan X, Sammeth M, Sandu KS, Schaeffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Hayashizaki Y, Reymond A, Antonarakis SE, Hannon GJ, Ruan Y, Carninci P, Sloan CA, Learned K, Malladi VS, Wong MC, Barber GP, Cline MS, Dreszer TR, Heitner SG, Karolchik D, Kirkup VM, Meyer LR, Long JC, Maddren M, Raney BJ, Grasfeder LL, Giresi PG, Battenhouse A, Sheffield NC, Showers KA, London D, Bhinge AA, Shestak C, Schaner MR, Kim SK, Zhang ZZ, Mieczkowski PA, Mieczkowska JO, Liu Z, McDaniell RM, Ni Y, Rashid NU, Kim MJ, Adar S, Zhang Z, Wang T, Winter D, Keefe D, Iyer VR, Sandhu KS, Zheng M, Wang P, Gertz J, Vielmetter J, Partridge EC, Varley KE, Gasper C, Bansal A, Pepke S, Jain P, Amrhein H, Bowling KM, Anaya M, Cross MK, Muratet MA, Newberry KM, McCue K, Nesmith AS, Fisher-Aylor KI, Pusey B, DeSalvo G, Parker SL, Balasubramanian S, Davis NS, Meadows SK, Eggleston T, Newberry JS, Levy SE, Absher DM, Wong WH, Blow MJ, Visel A, Pennachio LA, Elnitski L, Petrykowska HM, Abyzov A, Aken B, Barrell D, Barson G, Berry A, Bignell A, Boychenko V, Bussotti G, Davidson C, Despacio-Reyes G, Diekhans M, Ezkurdia I, Frankish A, Gilbert J, Gonzalez JM, Griffiths E, Harte R, Hendrix DA, Hunt T, Jungreis I, Kay M, Khurana E, Leng J, Lin MF, Loveland J, Lu Z, Manthravadi D, Mariotti M, Mudge J, Mukherjee G, Notredame C, Pei B, Rodriguez JM, Saunders G, Sboner A, Searle S, Sisu C, Snow C, Steward C, Tapanari E, Tress ML, van Baren MJ, Washieti S, Wilming L, Zadissa A, Zhengdong Z, Brent M, Haussler D, Valencia A, Raymond A, Addleman N, Alexander RP, Auerbach RK, Bettinger K, Bhardwaj N, Boyle AP, Cao AR, Cayting P, Charos A, Cheng Y, Eastman C, Euskirchen G, Fleming JD, Grubert F, Habegger L, Hariharan M, Harmanci A, Iyenger S, Jin VX, Karczewski KJ, Kasowski M, Lacroute P, Lam H, Larnarre-Vincent N, Lian J, Lindahl-Allen M, Min R, Miotto B, Monahan H, Moqtaderi Z, Mu XJ, O’Geen H, Ouyang Z, Patacsil D, Raha D, Ramirez L, Reed B, Shi M, Slifer T, Witt H, Wu L, Xu X, Yan KK, Yang X, Struhl K, Weissman SM, Tenebaum SA, Penalva LO, Karmakar S, Bhanvadia RR, Choudhury A, Domanus M, Ma L, Moran J, Victorsen A, Auer T, Centarin L, Eichenlaub M, Gruhl F, Heerman S, Hoeckendorf B, Inoue D, Kellner T, Kirchmaier S, Mueller C, Reinhardt R, Schertel L, Schneider S, Sinn R, Wittbrodt B, Wittbrodt J, Jain G, Balasundaram G, Bates DL, Byron R, Canfield TK, Diegel MJ, Dunn D, Ebersol AK, Frum T, Garg K, Gist E, Hansen RS, Boatman L, Haugen E, Humbert R, Johnson AK, Johnson EM, Kutyavin TM, Lee K, Lotakis D, Maurano MT, Neph SJ, Neri FV, Nguyen ED, Qu H, Reynolds AP, Roach V, Rynes E, Sanchez ME, Sandstrom RS, Shafer AO, Stergachis AB, Thomas S, Vernot B, Vierstra J, Vong S, Weaver MA, Yan Y, Zhang M, Akey JA, Bender M, Dorschner MO, Groudine M, MacCoss MJ, Navas P, Stamatoyannopoulos G, Stamatoyannopoulos JA, Beal K, Brazma A, Flicek P, Johnson N, Lukk M, Luscombe NM, Sobral D, Vaquerizas JM, Batzoglou S, Sidow A, Hussami N, Kyriazopoulou-Panagiotopoulou S, Libbrecht MW, Schaub MA, Miller W, Bickel PJ, Banfai B, Boley NP, Huang H, Li JJ, Noble WS, Bilmes JA, Buske OJ, Sahu AO, Kharchenko PV, Park PJ, Baker D, Taylor J, Lochovsky L (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74. doi:10.1038/nature11247
Fakharzadeh SS, Trusko SP, George DL (1991) Tumorigenic potential associated with enhanced expression of a gene that is amplified in a mouse tumor cell line. Embo J 10(6):1565–1569
Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J (1996) Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 2(8):912–917
Bartl S, Ban J, Weninger H, Jug G, Kovar H (2003) A small nuclear RNA, hdm365, is the major processing product of the human mdm2 gene. Nucleic Acids Res 31(4):1136–1147
Sam KK, Gan CP, Yee PS, Chong CE, Lim KP, Karen-Ng LP, Chang WS, Nathan S, Rahman ZA, Ismail SM, Cheong SC (2012) Novel MDM2 splice variants identified from oral squamous cell carcinoma. Oral Oncol 48(11):1128–1135. doi:10.1016/j.oraloncology.2012.05.016
Yu Z, Zhang B, Cui B, Wang Y, Han P, Wang X (2012) Identification of spliced variants of the proto-oncogene HDM2 in colorectal cancer. Cancer 118(4):1110–1118. doi:10.1002/cncr.26330
Bartel F, Taylor AC, Taubert H, Harris LC (2001) Novel mdm2 splice variants identified in pediatric rhabdomyosarcoma tumors and cell lines. Oncol Res 12(11–12):451–457
Schlott T, Nagel H, Laskawi R, Eiffert H, Droese M (2001) Genetic analysis of the human oncoprotein MDM2 in benign and malignant tumors of the salivary gland. Pathobiology 69(2):67–76
Lukas J, Gao DQ, Keshmeshian M, Wen WH, Tsao-Wei D, Rosenberg S, Press MF (2001) Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res 61(7):3212–3219
Hori M, Shimazaki J, Inagawa S, Itabashi M (2000) Alternatively spliced MDM2 transcripts in human breast cancer in relation to tumor necrosis and lymph node involvement. Pathol Int 50(10):786–792
Tamborini E, Della Torre G, Lavarino C, Azzarelli A, Carpinelli P, Pierotti MA, Pilotti S (2001) Analysis of the molecular species generated by MDM2 gene amplification in liposarcomas. Int J Cancer 92(6):790–796. doi:10.1002/ijc.1271
Kraus A, Neff F, Behn M, Schuermann M, Muenkel K, Schlegel J (1999) Expression of alternatively spliced mdm2 transcripts correlates with stabilized wild-type p53 protein in human glioblastoma cells. Int J Cancer 80(6):930–934
Arva NC, Talbott KE, Okoro DR, Brekman A, Qiu WG, Bargonetti J (2008) Disruption of the p53-Mdm2 complex by Nutlin-3 reveals different cancer cell phenotypes. Ethn Dis 18(2 Suppl 2):S2-1–8
Bartel F, Meye A, Wurl P, Kappler M, Bache M, Lautenschlager C, Grunbaum U, Schmidt H, Taubert H (2001) Amplification of the MDM2 gene, but not expression of splice variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma. Int J Cancer 95(3):168–175
Evans SC, Viswanathan M, Grier JD, Narayana M, El-Naggar AK, Lozano G (2001) An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 20(30):4041–4049. doi:10.1038/sj.onc.1204533
Anderson JJ, Challen C, Atkins H, Suaeyun R, Crosier S, Lunec J (2007) MDM2 RNA binding is blocked by novel monoclonal antibody h-MDM2-F4-14. Int J Oncol 31(3):545–555
Matsumoto R, Tada M, Nozaki M, Zhang CL, Sawamura Y, Abe H (1998) Short alternative splice transcripts of the mdm2 oncogene correlate to malignancy in human astrocytic neoplasms. Cancer Res 58(4):609–613
Liang H, Atkins H, Abdel-Fattah R, Jones SN, Lunec J (2004) Genomic organisation of the human MDM2 oncogene and relationship to its alternatively spliced mRNAs. Gene 338(2):217–223
Chandler DS, Singh RK, Caldwell LC, Bitler JL, Lozano G (2006) Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. Cancer Res 66(19):9502–9508. doi:10.1158/0008-5472.CAN-05-4271
Okoro DR, Rosso M, Bargonetti J (2012) Splicing up mdm2 for cancer proteome diversity. Genes Cancer 3(3–4):311–319. doi:10.1177/1947601912455323
Dias C, Liu Y, Yau A, Westrick L, Evans S (2006) Regulation of hdm2 by stress-induced hdm2alt1 in tumor and nontumorigenic cell lines correlating with p53 stability. Cancer Res 66(19):9467–9473
Dias CS, Liu Y, Yau A, Westrick L, Evans SC (2006) Regulation of hdm2 by stress-induced hdm2alt1 in tumor and nontumorigenic cell lines correlating with p53 stability. Cancer Res 66(19):9467–9473. doi:10.1158/0008-5472.CAN-05-3013
Sanchez-Aguilera A, Garcia JF, Sanchez-Beato M, Piris MA (2006) Hodgkin’s lymphoma cells express alternatively spliced forms of HDM2 with multiple effects on cell cycle control. Oncogene 25(18):2565–2574. doi:10.1038/sj.onc.1209282
Weng MW, Lai JC, Hsu CP, Yu KY, Chen CY, Lin TS, Lai WW, Lee H, Ko JL (2005) Alternative splicing of MDM2 mRNA in lung carcinomas and lung cell lines. Environ Mol Mutagen 46(1):1–11. doi:10.1002/em.20118
Zauberman A, Flusberg D, Haupt Y, Barak Y, Oren M (1995) A functional p53-responsive intronic promoter is contained within the human mdm2 gene. Nucleic Acids Res 23(14):2584–2592
Busuttil V, Droin N, McCormick L, Bernassola F, Candi E, Melino G, Green DR (2010) NF-kappaB inhibits T-cell activation-induced, p73-dependent cell death by induction of MDM2. Proc Natl Acad Sci U S A 107(42):18061–18066. doi:10.1073/pnas.1006163107
Barak Y, Gottlieb E, Juven-Gershon T, Oren M (1994) Regulation of mdm2 expression by p53: alternative promoters produce transcripts with nonidentical translation potential. Genes Dev 8:1739–1749
Manfredi J (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24(15):1580–1589, 24/15/1580 [pii]. doi:10.1101/gad.1941710
Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M, McCormick F (2000) Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell 103(2):321–330
Slack A, Lozano G, Shohet JM (2005) MDM2 as MYCN transcriptional target: implications for neuroblastoma pathogenesis. Cancer letters 228(1–2):21–27, S0304-3835(05)00350-2 [pii]. doi:10.1016/j.canlet.2005.01.050
Araki S, Eitel JA, Batuello CN, Bijangi-Vishehsaraei K, Xie XJ, Danielpour D, Pollok KE, Boothman DA, Mayo LD (2010) TGF-beta1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer. J Clin Invest 120(1):290–302. doi:10.1172/JCI39194
Bond G, Hu W, Bond E, Robins H, Lutzker S, Arva N, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang S, Strong L, Lozano G, Levine A (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602
Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110
Xu X, Fang Y, Lee T, Forrest D, Gregory-Evans C, Almeida D, Liu A, Jhanwar S, Abramson D, Cobrinik D (2009) Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137(6):1018–1031, S0092-8674(09)00400-0 [pii]. doi:10.1016/j.cell.2009.03.051
Brekman A, Singh KE, Polotskaia A, Kundu N, Bargonetti J (2011) A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res: BCR 13(1):R3. doi:10.1186/bcr2804
Phelps M, Darley M, Primrose JN, Blaydes JP (2003) p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells. Cancer Res 63(10):2616–2623
Singh RK, Tapia-Santos A, Bebee TW, Chandler DS (2009) Conserved sequences in the final intron of MDM2 are essential for the regulation of alternative splicing of MDM2 in response to stress. Exp Cell Res 315(19):3419–3432. doi:10.1016/j.yexcr.2009.07.017
Dutertre M, Sanchez G, De Cian MC, Barbier J, Dardenne E, Gratadou L, Dujardin G, Le Jossic-Corcos C, Corcos L, Auboeuf D (2010) Cotranscriptional exon skipping in the genotoxic stress response. Nat Struct Mol Biol 17(11):1358–1366. doi:10.1038/nsmb.1912
Steinman HA, Burstein E, Lengner C, Gosselin J, Pihan G, Duckett CS, Jones SN (2004) An alternative splice form of Mdm2 induces p53-independent cell growth and tumorigenesis. J Biol Chem 279(6):4877–4886
Volk EL, Schuster K, Nemeth KM, Fan L, Harris LC (2009) MDM2-A, a common Mdm2 splice variant, causes perinatal lethality, reduced longevity and enhanced senescence. Dis Model Mech 2(1–2):47–55. doi:10.1242/dmm.000992
Volk EL, Fan L, Schuster K, Rehg JE, Harris LC (2009) The MDM2-a splice variant of MDM2 alters transformation in vitro and the tumor spectrum in both Arf- and p53-null models of tumorigenesis. Mol Cancer Res 7(6):863–869. doi:10.1158/1541-7786.MCR-08-0418
Okoro D, Arva N, Gao C, Polotskaia A, Puente C, Rosso M, Bargonetti J (2013) Endogenous human MDM2-C is highly expressed in human cancers and functions as a p53-independent growth activator. PLoS One 8(10):e77643
Evans S, Viswanathan M, Grier J, Narayana M, El-Naggar A, Lozano G (2001) An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 20(30):4041–4049
Haupt Y, Maya R, Kazaz A, Oren M (1997) Mdm2 promotes the rapid degradation of p53. Nature 387:296–299
Naski N, Gajjar M, Bourougaa K, Malbert-Colas L, Fahraeus R, Candeias MM (2009) The p53 mRNA-Mdm2 interaction. Cell Cycle 8(1):31–34
Ghigna C, Valacca C, Biamonti G (2008) Alternative splicing and tumor progression. Curr Genomics 9(8):556–570. doi:10.2174/138920208786847971
Kalnina Z, Zayakin P, Silina K, Line A (2005) Alterations of pre-mRNA splicing in cancer. Genes Chromosomes Cancer 42(4):342–357. doi:10.1002/gcc.20156
David CJ, Manley JL (2010) Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 24(21):2343–2364. doi:10.1101/gad.1973010
Grosso AR, Martins S, Carmo-Fonseca M (2008) The emerging role of splicing factors in cancer. EMBO Rep 9(11):1087–1093. doi:10.1038/embor.2008.189
David CJ, Chen M, Assanah M, Canoll P, Manley JL (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463(7279):364–368. doi:10.1038/nature08697
Chansky HA, Hu M, Hickstein DD, Yang L (2001) Oncogenic TLS/ERG and EWS/Fli-1 fusion proteins inhibit RNA splicing mediated by YB-1 protein. Cancer Res 61(9):3586–3590
Petermann R, Mossier BM, Aryee DN, Khazak V, Golemis EA, Kovar H (1998) Oncogenic EWS-Fli1 interacts with hsRPB7, a subunit of human RNA polymerase II. Oncogene 17(5):603–610. doi:10.1038/sj.onc.1201964
Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B (1993) p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 53(10 Suppl):2231–2234
Hori M, Shimazaki J, Inagawa S, Itabashi M (2002) Overexpression of MDM2 oncoprotein correlates with possession of estrogen receptor alpha and lack of MDM2 mRNA splice variants in human breast cancer. Breast Cancer Res Treat 71(1):77–83
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Rosso, M., Okoro, D.E., Bargonetti, J. (2014). Splice Variants of MDM2 in Oncogenesis. In: Deb, S., Deb, S. (eds) Mutant p53 and MDM2 in Cancer. Subcellular Biochemistry, vol 85. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9211-0_14
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