When MAGE meets RING: insights into biological functions of MAGE proteins

Abstract

The melanoma antigen (MAGE) family proteins are well known as tumor-specific antigens and comprise more than 60 genes, which share a conserved MAGE homology domain (MHD). Type I MAGEs are highly expressed cancer antigens, and they play an important role in tumorigenesis and cancer cell survival. Recently, several MAGE proteins were identified to interact with RING domain proteins, including a sub-family of E3 ubiquitin ligases. The binding mode between MAGEs and RING proteins was investigated and one important structure of these MAGE-RING complexes was solved: the MAGE-G1-NSE1 complex. Structural and biochemical studies indicated that MAGE proteins could adjust the E3 ubiquitin ligase activity of its cognate RING partner both in vitro and in vivo. However, the underlying mechanism was not fully understood. Here, we review these exciting advances in the studies on MAGE family, suggest potential mechanisms by which MAGEs activate the E3 activity of their binding RING proteins and highlight the anticancer potential of this family proteins.

Keywords

MAGE / cancer testis antigen / RING / ubiquitin ligase / TRIM28

References

[1] BarkerP.A., and SalehiA., (2002). The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res 67, 705–712 .11891783
[2] BolliM., KocherT., AdaminaM., GullerU., DalquenP., HaasP.,, MirlacherM., GambazziF., HarderF., HebererM., (2002). Tissue microarray evaluation of Melanoma antigen E (MAGE) tumor-associated antigen expression: potential indications for specific immunotherapy and prognostic relevance in squamous cell lung carcinoma. Ann Surg 236, 785–793 , discussion 793.12454517
[3] BordenK.L., (2000). RING domains: master builders of molecular scaffolds? J Mol Biol 295, 1103–1112 .10653689
[4] BrasseurF., RimoldiD., LiénardD., LethéB., CarrelS., ArientiF., SuterL., VanwijckR., BourlondA., HumbletY., (1995). Expression of MAGE genes in primary and metastatic cutaneous melanoma. Int J Cancer 63, 375–380 .7591235
[5] BrichardV.G., and LejeuneD., (2007). GSK’s antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine 25, B61–B71 .17916463
[6] ChomezP., De BackerO., BertrandM., De PlaenE., BoonT., and LucasS., (2001). An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res 61, 5544–5551 .11454705
[7] CilensekZ.M., YehielyF., KularR.K., and DeissL.P., (2002). A member of the GAGE family of tumor antigens is an anti-apoptotic gene that confers resistance to Fas/CD95/APO-1, Interferon-gamma, taxol and gamma-irradiation. Cancer Biol Ther 1, 380–387 .12432251
[8] ColalucaI.N., TosoniD., NuciforoP., Senic-MatugliaF., GalimbertiV., VialeG., PeceS., and Di FioreP.P., (2008). NUMB controls p53 tumour suppressor activity. Nature 451, 76–80 .18172499
[9] De SmetC., CourtoisS.J., FaraoniI., LurquinC., SzikoraJ.P., De BackerO., and BoonT., (1995). Involvement of two Ets binding sites in the transcriptional activation of the MAGE1 gene. Immunogenetics 42, 282–290 .7672823
[10] Di CertoM.G., CorbiN., BrunoT., IezziS., De NicolaF., DesantisA., CiottiM.T., MatteiE., FloridiA., FanciulliM., (2007). NRAGE associates with the anti-apoptotic factor Che-1 and regulates its degradation to induce cell death. J Cell Sci 120, 1852–1858 .17488777
[11] DoyleJ.M., GaoJ., WangJ., YangM., and PottsP.R., (2010). MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell 39, 963–974 .20864041
[12] DuanZ., DuanY., LamendolaD.E., YusufR.Z., NaeemR., PensonR.T., and SeidenM.V., (2003). Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res 9, 2778–2785 .12855658
[13] EspantmanK.C., and O’SheaC.C., (2010). aMAGEing new players enter the RING to promote ubiquitylation. Mol Cell 39, 835–837 .20864031
[14] GoldmanB., and DeFrancescoL., (2009). The cancer vaccine roller coaster. Nat Biotechnol 27, 129–139 .19204689
[15] JacksonP.K., EldridgeA.G., FreedE., FurstenthalL., HsuJ.Y., KaiserB.K., and ReimannJ.D., (2000). The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 10, 429–439 .10998601
[16] JordanB.W., DinevD., LeMellayV., TroppmairJ., GotzR., WixlerL., SendtnerM., LudwigS., and RappU.R., (2001). Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death. J Biol Chem 276, 39985–39989 .11546791
[17] KendallS.E., BattelliC., IrwinS., MitchellJ.G., GlackinC.A., and VerdiJ.M., (2005). NRAGE mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade. Mol Cell Biol 25, 7711–7724 .16107717
[18] LiuY., ZhuQ., and ZhuN., (2008). Recent duplication and positive selection of the GAGE gene family. Genetica 133, 31–35 .17661182
[19] López-SánchezN., González-FernándezZ., NiinobeM., YoshikawaK., and FradeJ.M., (2007). Single mage gene in the chicken genome encodes CMage, a protein with functional similarities to mammalian type II Mage proteins. Physiol Genomics 30, 156–171 .17374844
[20] LorickK.L., JensenJ.P., FangS., OngA.M., HatakeyamaS., and WeissmanA.M., (1999). RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96, 11364–11369 .10500182
[21] MeroniG., and Diez-RouxG., (2005). TRIM/RBCC, a novel class of ‘single protein RING finger’ E3 ubiquitin ligases.Bioessays 27, 1147–1157 .16237670
[22] MirandaE.I., (2010). MAGE, biological functions and potential clinical applications. Leuk Res 34, 1121–1122 .20452019
[23] MoonH.E., AhnM.Y., ParkJ.A., MinK.J., KwonY.W., and KimK.W., (2005). FEBS Lett 579, 3797–3801 .15978586
[24] NasmythK., and HaeringC.H., (2005). The structure and function of SMC and kleisin complexes. Annu Rev Biochem 74, 595–648 .15952899
[25] NieJ., McGillM.A., DermerM., DhoS.E., WoltingC.D., and McGladeC.J., (2002). LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. EMBO J 21, 93–102 .11782429
[26] Ohman ForslundK., and NordqvistK., (2001). The melanoma antigen genes—any clues to their functions in normal tissues? Exp Cell Res 265, 185–194 .11302683
[27] ParkJ.H., KongG.H., and LeeS.W., (2002). hMAGE-A1 overexpression reduces TNF-alpha cytotoxicity in ME-180 cells. Mol Cells 14, 122–129 .12243341
[28] PatardJ.J., BrasseurF., Gil-DiezS., RadvanyiF., MarchandM., Fran?oisP., Abi-AadA., Van CanghP., AbbouC.C., ChopinD., (1995). Expression of MAGE genes in transitional-cell carcinomas of the urinary bladder. Int J Cancer 64, 60–64 .7665250
[29] PawsonT., and NashP., (2003). Assembly of cell regulatory systems through protein interaction domains. Science 300, 445–452 .12702867
[30] PebernardS., McDonaldW.H., PavlovaY., YatesJ.R., 3rd, and BoddyM.N., (2004). Nse1, Nse2, and a novel subunit of the Smc5-Smc6 complex, Nse3, play a crucial role in meiosis. Mol Biol Cell 15, 4866–4876 .15331764
[31] PebernardS., PerryJ.J., TainerJ.A., and BoddyM.N., (2008). Nse1 RING-like domain supports functions of the Smc5-Smc6 holocomplex in genome stability. Mol Biol Cell 19, 4099–4109 .18667531
[32] PottsP.R., (2009). The Yin and Yang of the MMS21-SMC5/6 SUMO ligase complex in homologous recombination. DNA Repair (Amst) 8, 499–506 .19217832
[33] RualJ.F., VenkatesanK., HaoT., Hirozane-KishikawaT., DricotA., LiN., BerrizG.F., GibbonsF.D., DrezeM., Ayivi-GuedehoussouN., (2005). Towards a proteome-scale map of the human protein-protein interaction network. Nature 437, 1173–1178 .16189514
[34] SasakiA., MasudaY., IwaiK., IkedaK., and WatanabeK., (2002). A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msx-interacting MAGE/Necdin family protein, Dlxin-1. J Biol Chem 277, 22541–22546 .11959851
[35] ScanlanM.J., GureA.O., JungbluthA.A., OldL.J., and ChenY.T., (2002). Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev 188, 22–32 .12445278
[36] ScanlanM.J., SimpsonA.J., and OldL.J., (2004). The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4, 1.14738373
[37] SergeantJ., TaylorE., PalecekJ., FousteriM., AndrewsE.A., SweeneyS., ShinagawaH., WattsF.Z., and LehmannA.R., (2005). Composition and architecture of the Schizosaccharomyces pombe Rad18 (Smc5-6) complex. Mol Cell Biol 25, 172–184 .15601840
[38] SimpsonA.J., CaballeroO.L., JungbluthA., ChenY.T., and OldL.J., (2005). Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5, 615–625 .16034368
[39] TaylorE.M., CopseyA.C., HudsonJ.J., VidotS., and LehmannA.R., (2008). Identification of the proteins, including MAGEG1, that make up the human SMC5-6 protein complex. Mol Cell Biol 28, 1197–1206 .18086888
[40] van der BruggenP., TraversariC., ChomezP., LurquinC., De PlaenE., Van den EyndeB., KnuthA., and BoonT., (1991). A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643–1647 .1840703
[41] VarfolomeevE., and VucicD., (2008). (Un)expected roles of c-IAPs in apoptotic and NFkappaB signaling pathways. Cell Cycle 7, 1511–1521 .18469528
[42] WangC., IvanovA., ChenL., FredericksW.J., SetoE., RauscherF.J., 3rd, and ChenJ., (2005). MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J 24, 3279–3290 .16107876
[43] YangB., O’HerrinS.M., WuJ., Reagan-ShawS., MaY., BhatK.M., GravekampC., SetaluriV., PetersN., HoffmannF.M., (2007). MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res 67, 9954–9962 .17942928
[44] ZhengN., SchulmanB.A., SongL., MillerJ.J., JeffreyP.D., WangP., ChuC., KoeppD.M., ElledgeS.J., PaganoM., (2002). Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 .11961546