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. 2011 Feb 20;2(1):7–12. doi: 10.1007/s13238-011-1002-9

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

Yue Feng 1,2, Jinlan Gao 1,3, Maojun Yang 1,2,✉
PMCID: PMC4875283  PMID: 21337005

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. Barker P.A., Salehi A. The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res. 2002;67:705–712. doi: 10.1002/jnr.10160. [DOI] [PubMed] [Google Scholar]
  2. Bolli M., Kocher T., Adamina M., Guller U., Dalquen P., Haas P., Mirlacher M., Gambazzi F., Harder F., Heberer M., et al. 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. 2002;236:785–793. doi: 10.1097/00000658-200212000-00011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Borden K.L. RING domains: master builders of molecular scaffolds? J Mol Biol. 2000;295:1103–1112. doi: 10.1006/jmbi.1999.3429. [DOI] [PubMed] [Google Scholar]
  4. Brasseur F., Rimoldi D., Liénard D., Lethé B., Carrel S., Arienti F., Suter L., Vanwijck R., Bourlond A., Humblet Y., et al. Expression of MAGE genes in primary and metastatic cutaneous melanoma. Int J Cancer. 1995;63:375–380. doi: 10.1002/ijc.2910630313. [DOI] [PubMed] [Google Scholar]
  5. Brichard V.G., Lejeune D. GSK’s antigen-specific cancer immunotherapy programme: pilot results leading to Phase III clinical development. Vaccine. 2007;25:B61–B71. doi: 10.1016/j.vaccine.2007.06.038. [DOI] [PubMed] [Google Scholar]
  6. Chomez P., De Backer O., Bertrand M., De Plaen E., Boon T., Lucas S. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 2001;61:5544–5551. [PubMed] [Google Scholar]
  7. Cilensek Z.M., Yehiely F., Kular R.K., Deiss L.P. A member of the GAGE family of tumor antigens is an anti-apoptotic gene that confers resistance to Fas/CD95/APO-1, Interferongamma, taxol and gamma-irradiation. Cancer Biol Ther. 2002;1:380–387. doi: 10.4161/cbt.1.4.11. [DOI] [PubMed] [Google Scholar]
  8. Colaluca I.N., Tosoni D., Nuciforo P., Senic-Matuglia F., Galimberti V., Viale G., Pece S., Di Fiore P.P. NUMB controls p53 tumour suppressor activity. Nature. 2008;451:76–80. doi: 10.1038/nature06412. [DOI] [PubMed] [Google Scholar]
  9. De Smet C., Courtois S.J., Faraoni I., Lurquin C., Szikora J.P., De Backer O., Boon T. Involvement of two Ets binding sites in the transcriptional activation of the MAGE1 gene. Immunogenetics. 1995;42:282–290. doi: 10.1007/BF00176446. [DOI] [PubMed] [Google Scholar]
  10. Di Certo M.G., Corbi N., Bruno T., Iezzi S., De Nicola F., Desantis A., Ciotti M.T., Mattei E., Floridi A., Fanciulli M., et al. NRAGE associates with the anti-apoptotic factor Che-1 and regulates its degradation to induce cell death. J Cell Sci. 2007;120:1852–1858. doi: 10.1242/jcs.03454. [DOI] [PubMed] [Google Scholar]
  11. Doyle J.M., Gao J., Wang J., Yang M., Potts P.R. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell. 2010;39:963–974. doi: 10.1016/j.molcel.2010.08.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Duan Z., Duan Y., Lamendola D.E., Yusuf R.Z., Naeem R., Penson R.T., Seiden M.V. Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res. 2003;9:2778–2785. [PubMed] [Google Scholar]
  13. Espantman K.C., O’shea C.C. aMAGEing new players enter the RING to promote ubiquitylation. Mol Cell. 2010;39:835–837. doi: 10.1016/j.molcel.2010.09.006. [DOI] [PubMed] [Google Scholar]
  14. Goldman B., DeFrancesco L. The cancer vaccine roller coaster. Nat Biotechnol. 2009;27:129–139. doi: 10.1038/nbt0209-129. [DOI] [PubMed] [Google Scholar]
  15. Jackson P.K., Eldridge A.G., Freed E., Furstenthal L., Hsu J.Y., Kaiser B.K., Reimann J.D. The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol. 2000;10:429–439. doi: 10.1016/S0962-8924(00)01834-1. [DOI] [PubMed] [Google Scholar]
  16. Jordan B.W., Dinev D., LeMellay V., Troppmair J., Gotz R., Wixler L., Sendtner M., Ludwig S., Rapp U.R. Neurotrophin receptor-interacting mage homologue is an inducible inhibitor of apoptosis protein-interacting protein that augments cell death. J Biol Chem. 2001;276:39985–39989. doi: 10.1074/jbc.C100171200. [DOI] [PubMed] [Google Scholar]
  17. Kendall S.E., Battelli C., Irwin S., Mitchell J.G., Glackin C.A., Verdi J.M. NRAGE mediates p38 activation and neural progenitor apoptosis via the bone morphogenetic protein signaling cascade. Mol Cell Biol. 2005;25:7711–7724. doi: 10.1128/MCB.25.17.7711-7724.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Liu Y., Zhu Q., Zhu N. Recent duplication and positive selection of the GAGE gene family. Genetica. 2008;133:31–35. doi: 10.1007/s10709-007-9179-9. [DOI] [PubMed] [Google Scholar]
  19. López-Sánchez N., González-Fernández Z., Niinobe M., Yoshikawa K., Frade J.M. Single mage gene in the chicken genome encodes CMage, a protein with functional similarities to mammalian type II Mage proteins. Physiol Genomics. 2007;30:156–171. doi: 10.1152/physiolgenomics.00249.2006. [DOI] [PubMed] [Google Scholar]
  20. Lorick K.L., Jensen J.P., Fang S., Ong A.M., Hatakeyama S., Weissman A.M. RING fingers mediate ubiquitinconjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A. 1999;96:11364–11369. doi: 10.1073/pnas.96.20.11364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Meroni G., Diez-Roux G. TRIM/RBCC, a novel class of ’single protein RING finger’ E3 ubiquitin ligases. Bioessays. 2005;27:1147–1157. doi: 10.1002/bies.20304. [DOI] [PubMed] [Google Scholar]
  22. Miranda E.I. MAGE, biological functions and potential clinical applications. Leuk Res. 2010;34:1121–1122. doi: 10.1016/j.leukres.2010.03.045. [DOI] [PubMed] [Google Scholar]
  23. Moon H.E., Ahn M.Y., Park J.A., Min K.J., Kwon Y.W., Kim K. W. Negative regulation of hypoxia inducible factor-lalpha by necdin. FEBS Lett. 2005;579:3797–3801. doi: 10.1016/j.febslet.2005.05.072. [DOI] [PubMed] [Google Scholar]
  24. Nasmyth K., Haering C.H. The structure and function of SMC and kleisin complexes. Annu Rev Biochem. 2005;74:595–648. doi: 10.1146/annurev.biochem.74.082803.133219. [DOI] [PubMed] [Google Scholar]
  25. Nie J., McGill M.A., Dermer M., Dho S.E., Wolting C.D., McGlade C.J. LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation. EMBO J. 2002;21:93–102. doi: 10.1093/emboj/21.1.93. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ohman Forslund K., Nordqvist K. The melanoma antigen genes-any clues to their functions in normal tissues? Exp Cell Res. 2001;265:185–194. doi: 10.1006/excr.2001.5173. [DOI] [PubMed] [Google Scholar]
  27. Park J.H., Kong G.H., Lee S.W. hMAGE-A1 over-expression reduces TNF-alpha cytotoxicity in ME-180 cells. Mol Cells. 2002;14:122–129. [PubMed] [Google Scholar]
  28. Patard J.J., Brasseur F., Gil-Diez S., Radvanyi F., Marchand M., François P., Abi-Aad A., Van Cangh P., Abbou C.C., Chopin D., et al. Expression of MAGE genes in transitional-cell carcinomas of the urinary bladder. Int J Cancer. 1995;64:60–64. doi: 10.1002/ijc.2910640112. [DOI] [PubMed] [Google Scholar]
  29. Pawson T., Nash P. Assembly of cell regulatory systems through protein interaction domains. Science. 2003;300:445–452. doi: 10.1126/science.1083653. [DOI] [PubMed] [Google Scholar]
  30. Pebernard S., McDonald W.H., Pavlova Y., Yates J.R., 3rd, Boddy M.N. Nse1, Nse2, and a novel subunit of the Smc5–Smc6 complex, Nse3, play a crucial role in meiosis. Mol Biol Cell. 2004;15:4866–4876. doi: 10.1091/mbc.E04-05-0436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pebernard S., Perry J.J., Tainer J.A., Boddy M.N. Nse1 RING-like domain supports functions of the Smc5-Smc6 holocomplex in genome stability. Mol Biol Cell. 2008;19:4099–4109. doi: 10.1091/mbc.E08-02-0226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Potts P.R. The Yin and Yang of the MMS21-SMC5/6 SUMO ligase complex in homologous recombination. DNA Repair (Amst) 2009;8:499–506. doi: 10.1016/j.dnarep.2009.01.009. [DOI] [PubMed] [Google Scholar]
  33. Rual J.F., Venkatesan K., Hao T., Hirozane-Kishikawa T., Dricot A., Li N., Berriz G.F., Gibbons F.D., Dreze M., Ayivi-Guedehoussou N., et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature. 2005;437:1173–1178. doi: 10.1038/nature04209. [DOI] [PubMed] [Google Scholar]
  34. Sasaki A., Masuda Y., Iwai K., Ikeda K., Watanabe K. A RING finger protein Praja1 regulates Dlx5-dependent transcription through its ubiquitin ligase activity for the Dlx/Msxinteracting MAGE/Necdin family protein, Dlxin-1. J Biol Chem. 2002;277:22541–22546. doi: 10.1074/jbc.M109728200. [DOI] [PubMed] [Google Scholar]
  35. Scanlan M.J., Gure A.O., Jungbluth A.A., Old L.J., Chen Y.T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 2002;188:22–32. doi: 10.1034/j.1600-065X.2002.18803.x. [DOI] [PubMed] [Google Scholar]
  36. Scanlan M.J., Simpson A.J., Old L.J. The cancer/testis genes: review, standardization, and commentary. Cancer Immun. 2004;4:1. [PubMed] [Google Scholar]
  37. Sergeant J., Taylor E., Palecek J., Fousteri M., Andrews E.A., Sweeney S., Shinagawa H., Watts F.Z., Lehmann A.R. Composition and architecture of the Schizosaccharomyces pombe Rad18 (Smc5–6) complex. Mol Cell Biol. 2005;25:172–184. doi: 10.1128/MCB.25.1.172-184.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Simpson A.J., Caballero O.L., Jungbluth A., Chen Y.T., Old L. J. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5:615–625. doi: 10.1038/nrc1669. [DOI] [PubMed] [Google Scholar]
  39. Taylor E.M., Copsey A.C., Hudson J.J., Vidot S., Lehmann A. R. Identification of the proteins, including MAGEG1, that make up the human SMC5–6 protein complex. Mol Cell Biol. 2008;28:1197–1206. doi: 10.1128/MCB.00767-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–1647. doi: 10.1126/science.1840703. [DOI] [PubMed] [Google Scholar]
  41. Varfolomeev E., Vucic D. (Un)expected roles of c-IAPs in apoptotic and NFkappaB signaling pathways. Cell Cycle. 2008;7:1511–1521. doi: 10.4161/cc.7.11.5959. [DOI] [PubMed] [Google Scholar]
  42. Wang C., Ivanov A., Chen L., Fredericks W.J., Seto E., Rauscher F.J., 3rd, Chen J. MDM2 interaction with nuclear corepressor KAP1 contributes to p53 inactivation. EMBO J. 2005;24:3279–3290. doi: 10.1038/sj.emboj.7600791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yang B., O’Herrin S.M., Wu J., Reagan-Shaw S., Ma Y., Bhat K. M., Gravekamp C., Setaluri V., Peters N., Hoffmann F.M., et al. MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. Cancer Res. 2007;67:9954–9962. doi: 10.1158/0008-5472.CAN-07-1478. [DOI] [PubMed] [Google Scholar]
  44. Zheng N., Schulman B.A., Song L., Miller J.J., Jeffrey P.D., Wang P., Chu C., Koepp D.M., Elledge S.J., Pagano M., et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature. 2002;416:703–709. doi: 10.1038/416703a. [DOI] [PubMed] [Google Scholar]

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