Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling

Oncogene volume 31, pages 4639–4646 (2012)Cite this article

Subjects

Abstract

Papillomavirus E6 oncoproteins associate with LXXLL motifs on target cellular proteins to alter their function. Using a proteomic approach, we found the E6 oncoproteins of cutaneous papillomaviruses Bovine Papillomavirus Type 1 (BPV-1) E6 and human papillomavirus (HPV) types 1 and 8 (1E6 and 8E6) associated with the MAML1 transcriptional co-activator. All three E6 proteins bind to an acidic LXXLL motif at the carboxy-terminus of MAML1 and repress transactivation by MAML1. MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells. BPV-1-induced papillomas show characteristics of repressed NOTCH signal transduction, including suprabasal expression of integrins, talin and basal type keratins, and delayed expression of the NOTCH-dependent HES1 transcription factor. These observations give rise to a model whereby papillomavirus oncoproteins, including BPV-1 E6, and the cancer-associated HPV-8 E6 repress NOTCH-induced transcription, thereby delaying keratinocyte differentiation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. zur Hausen H . Papillomaviruses in the causation of human cancers - a brief historical account. Virology 2009; 384: 260–265.

    Article  CAS  PubMed  Google Scholar 

  2. Rous P, Beard JW . The progression to carcinoma of virus-induced rabbit Papillomas (Shope). J Exp Med 1935; 62: 523–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Orth G . Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses. Semin Immunol 2006; 18: 362–374.

    Article  CAS  PubMed  Google Scholar 

  4. Green H . Terminal differentiation of cultured human epidermal cells. Cell 1977; 11: 405–416.

    Article  CAS  PubMed  Google Scholar 

  5. Adams JC, Watt FM . Fibronectin inhibits the terminal differentiation of human keratinocytes. Nature 1989; 340: 307–309.

    Article  CAS  PubMed  Google Scholar 

  6. Watt FM, Kubler MD, Hotchin NA, Nicholson LJ, Adams JC . Regulation of keratinocyte terminal differentiation by integrin-extracellular matrix interactions. J Cell Sci 1993; 106 (Pt 1): 175–182.

    CAS  PubMed  Google Scholar 

  7. Dotto GP . Notch tumor suppressor function. Oncogene 2008; 27: 5115–5123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Watt FM, Estrach S, Ambler CA . Epidermal notch signalling: differentiation, cancer and adhesion. Curr Opin Cell Biol 2008; 20: 171–179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001; 20: 3427–3436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blanpain C, Lowry WE, Pasolli HA, Fuchs E . Canonical Notch signaling functions as a commitment switch in the epidermal lineage. Genes Dev 2006; 20: 3022–3035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moriyama M, Durham AD, Moriyama H, Hasegawa K, Nishikawa S, Radtke F et al. Multiple roles of Notch signaling in the regulation of epidermal development. Dev Cell 2008; 14: 594–604.

    Article  CAS  PubMed  Google Scholar 

  12. Tanigaki K, Honjo T . Two opposing roles of RBP-J in Notch signaling. Curr Top Dev Biol 2010; 92: 231–252.

    Article  CAS  PubMed  Google Scholar 

  13. Artavanis-Tsakonas S, Muskavitch MA . Notch: the past, the present, and the future. Curr Top Dev Biol 2010; 92: 1–29.

    Article  CAS  PubMed  Google Scholar 

  14. Saint Just Ribeiro M, Wallberg AE . Transcriptional mechanisms by the coregulator MAML1. Curr Protein Pept Sci 2009; 10: 570–576.

    Article  CAS  PubMed  Google Scholar 

  15. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD . MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000; 26: 484–489.

    Article  CAS  PubMed  Google Scholar 

  16. Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA . Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 2002; 16: 1397–1411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Saint Just Ribeiro M, Hansson ML, Wallberg AE . A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1. Biochem J 2007; 404: 289–298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chow LT, Broker TR . Papillomavirus DNA replication. Intervirology 1994; 37: 150–158.

    Article  CAS  PubMed  Google Scholar 

  19. Stubenrauch F, Laimins LA . Human papillomavirus life cycle: active and latent phases. Semin Cancer Biol 1999; 9: 379–386.

    Article  CAS  PubMed  Google Scholar 

  20. Chen JJ, Hong Y, Rustamzadeh E, Baleja JD, Androphy EJ . Identification of an alpha helical motif sufficient for association with papillomavirus E6. J Biol Chem 1998; 273: 13537–13544.

    Article  CAS  PubMed  Google Scholar 

  21. Elston RC, Napthine S, Doorbar J . The identification of a conserved binding motif within human papillomavirus type 16 E6 binding peptides, E6AP and E6BP. J Gen Virol 1998; 79 (Pt 2): 371–374.

    Article  CAS  PubMed  Google Scholar 

  22. Vande Pol SB, Brown MC, Turner CE . Association of bovine papillomavirus type 1 E6 oncoprotein with the focal adhesion protein paxillin through a conserved protein interaction motif. Oncogene 1998; 16: 43–52.

    Article  CAS  PubMed  Google Scholar 

  23. Tong X, Boll W, Kirchhausen T, Howley PM . Interaction of the bovine papillomavirus E6 protein with the clathrin adaptor complex AP-1. J Virol 1998; 72: 476–482.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tong X, Howley PM . The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton. Proc Natl Acad Sci USA 1997; 94: 4412–4417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bohl J, Das K, Dasgupta B, Vande Pol SB . Competitive binding to a charged leucine motif represses transformation by a papillomavirus E6 oncoprotein. Virology 2000; 271: 163–170.

    Article  CAS  PubMed  Google Scholar 

  26. Wade R, Brimer N, Vande Pol S . Transformation by bovine papillomavirus type 1 E6 requires paxillin. J Virol 2008; 82: 5962–5966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ronco LV, Karpova AY, Vidal M, Howley PM . Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity. Genes Dev 1998; 12: 2061–2072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huibregtse JM, Scheffner M, Howley PM . Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol 1993; 13: 4918–4927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Huibregtse JM, Scheffner M, Howley PM . A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J 1991; 10: 4129–4135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Huibregtse JM, Scheffner M, Howley PM . Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol 1993; 13: 775–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Scheffner M, Huibregtse JM, Howley PM . Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. Proc Natl Acad Sci USA 1994; 91: 8797–8801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Scheffner M, Huibregtse JM, Vierstra RD, Howley PM . The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993; 75: 495–505.

    Article  CAS  PubMed  Google Scholar 

  33. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM . The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990; 63: 1129–1136.

    Article  CAS  PubMed  Google Scholar 

  34. Das K, Bohl J, Vande Pol SB . Identification of a second transforming region in bovine papillomavirus type 1 E6 and the role of E6 interaction with paxilin, E6BP, and E6AP. J Virol 2000; 74: 812–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cooper B, Brimer N, Stoler M, Vande Pol SB . Suprabasal overexpression of beta-1 integrin is induced by bovine papillomavirus type 1. Virology 2006; 355: 102–114.

    Article  CAS  PubMed  Google Scholar 

  36. Kaiser HW, Ness W, Offers M, O’Keefe EJ, Kreysel HW . Talin: adherens junction protein is localized at the epidermal-dermal interface in skin. J Invest Dermatol 1993; 101: 789–793.

    Article  CAS  PubMed  Google Scholar 

  37. Yedvobnick B, Smoller D, Young P, Mills D . Molecular analysis of the neurogenic locus mastermind of Drosophila melanogaster. Genetics 1988; 118: 483–497.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Nicolas M, Wolfer A, Raj K, Kummer JA, Mill P, van Noort M et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet 2003; 33: 416–421.

    Article  CAS  PubMed  Google Scholar 

  39. Pan Y, Lin MH, Tian X, Cheng HT, Gridley T, Shen J et al. Gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 2004; 7: 731–743.

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto N, Tanigaki K, Han H, Hiai H, Honjo T . Notch/RBP-J signaling regulates epidermis/hair fate determination of hair follicular stem cells. Curr Biol 2003; 13: 333–338.

    Article  CAS  PubMed  Google Scholar 

  41. Proweller A, Tu L, Lepore JJ, Cheng L, Lu MM, Seykora J et al. Impaired Notch signaling promotes de novo squamous cell carcinoma formation. Cancer Res 2006; 66: 7438–7444.

    Article  CAS  PubMed  Google Scholar 

  42. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475: 101–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991; 66: 649–661.

    Article  CAS  PubMed  Google Scholar 

  44. Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G et al. Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 2009; 100: 920–926.

    Article  CAS  PubMed  Google Scholar 

  45. Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 2011; 473: 230–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011; 333: 1154–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157–1160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Baldus CD, Thibaut J, Goekbuget N, Stroux A, Schlee C, Mossner M et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica 2009; 94: 1383–1390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Daniel B, Rangarajan A, Mukherjee G, Vallikad E, Krishna S . The link between integration and expression of human papillomavirus type 16 genomes and cellular changes in the evolution of cervical intraepithelial neoplastic lesions. J Gen Virol 1997; 78 (Pt 5): 1095–1101.

    Article  CAS  PubMed  Google Scholar 

  50. Zagouras P, Stifani S, Blaumueller CM, Carcangiu ML, Artavanis-Tsakonas S . Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA 1995; 92: 6414–6418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ramdass B, Maliekal TT, Lakshmi S, Rehman M, Rema P, Nair P et al. Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression. Gynecol Oncol 2007; 104: 352–361.

    Article  CAS  PubMed  Google Scholar 

  52. Rangarajan A, Syal R, Selvarajah S, Chakrabarti O, Sarin A, Krishna S . Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology 2001; 286: 23–30.

    Article  CAS  PubMed  Google Scholar 

  53. Pang RT, Leung CO, Ye TM, Liu W, Chiu PC, Lam KK et al. MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. Carcinogenesis 2010; 31: 1037–1044.

    Article  CAS  PubMed  Google Scholar 

  54. Rasul S, Balasubramanian R, Filipovic A, Slade MJ, Yague E, Coombes RC . Inhibition of gamma-secretase induces G2/M arrest and triggers apoptosis in breast cancer cells. Br J Cancer 2009; 100: 1879–1888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sun XM, Wen HW, Chen CL, Liao QP . [Expression of Notch intracellular domain in cervical cancer and effect of DAPT on cervical cancer cell]. Zhonghua Fu Chan Ke Za Zhi 2009; 44: 369–373.

    CAS  PubMed  Google Scholar 

  56. Yu H, Huang SL, Zhao XP, Lu J, Qian GX, Ge SF . [Effect of CRE-dependent RNA interference targeting Notch1 on proliferation of cervical cancer cell line HeLa]. Ai Zheng 2007; 26: 148–153.

    CAS  PubMed  Google Scholar 

  57. Song LL, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S et al. Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells. Oncogene 2008; 27: 5833–5844.

    Article  CAS  PubMed  Google Scholar 

  58. Talora C, Cialfi S, Segatto O, Morrone S, Kim Choi J, Frati L et al. Constitutively active Notch1 induces growth arrest of HPV-positive cervical cancer cells via separate signaling pathways. Exp Cell Res 2005; 305: 343–354.

    Article  CAS  PubMed  Google Scholar 

  59. Talora C, Sgroi DC, Crum CP, Dotto GP . Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 2002; 16: 2252–2263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang L, Qin H, Chen B, Xin X, Li J, Han H . Overexpressed active Notch1 induces cell growth arrest of HeLa cervical carcinoma cells. Int J Gynecol Cancer 2007; 17: 1283–1292.

    Article  CAS  PubMed  Google Scholar 

  61. Yao J, Duan L, Fan M, Yuan J, Wu X . Notch1 induces cell cycle arrest and apoptosis in human cervical cancer cells: involvement of nuclear factor kappa B inhibition. Int J Gynecol Cancer 2007; 17: 502–510.

    Article  CAS  PubMed  Google Scholar 

  62. Lathion S, Schaper J, Beard P, Raj K . Notch1 can contribute to viral-induced transformation of primary human keratinocytes. Cancer Res 2003; 63: 8687–8694.

    CAS  PubMed  Google Scholar 

  63. Kurooka H, Honjo T . Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem 2000; 275: 17211–17220.

    Article  CAS  PubMed  Google Scholar 

  64. Wallberg AE, Pedersen K, Lendahl U, Roeder RG . p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Mol Cell Biol 2002; 22: 7812–7819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Oswald F, Tauber B, Dobner T, Bourteele S, Kostezka U, Adler G et al. p300 acts as a transcriptional coactivator for mammalian Notch-1. Mol Cell Biol 2001; 21: 7761–7774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhao Y, Katzman RB, Delmolino LM, Bhat I, Zhang Y, Gurumurthy CB et al. The Notch regulator MAML1 interacts with p53 and functions as a coactivator. J Biol Chem 2007; 282: 11969–11981.

    Article  CAS  PubMed  Google Scholar 

  67. Shen H, McElhinny AS, Cao Y, Gao P, Liu J, Bronson R et al. The Notch coactivator, MAML1, functions as a novel coactivator for MEF2C-mediated transcription and is required for normal myogenesis. Genes Dev 2006; 20: 675–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Alves-Guerra MC, Ronchini C, Capobianco AJ . Mastermind-like 1 is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival. Cancer Res 2007; 67: 8690–8698.

    Article  CAS  PubMed  Google Scholar 

  69. Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev 2007; 21: 562–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Melar-New M, Laimins LA . Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins. J Virol 2010; 84: 5212–5221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Allen-Hoffmann BL, Schlosser SJ, Ivarie CA, Sattler CA, Meisner LF, O’Connor SL . Normal growth and differentiation in a spontaneously immortalized near- diploid human keratinocyte cell line, NIKS. J Invest Dermatol 2000; 114: 444–455.

    Article  CAS  PubMed  Google Scholar 

  72. Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD . Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 1996; 16: 952–959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kutner RH, Zhang XY, Reiser J . Production, concentration and titration of pseudotyped HIV-1-based lentiviral vectors. Nat Protoc 2009; 4: 495–505.

    Article  CAS  PubMed  Google Scholar 

  74. Jin YH, Kim H, Oh M, Ki H, Kim K . Regulation of Notch1/NICD and Hes1 expressions by GSK-3alpha/beta. Mol Cells 2009; 27: 15–19.

    Article  CAS  PubMed  Google Scholar 

  75. Ohashi S, Natsuizaka M, Yashiro-Ohtani Y, Kalman RA, Nakagawa M, Wu L et al. NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network. Gastroenterology 2010; 139: 2113–2123.

    Article  CAS  PubMed  Google Scholar 

  76. Peng S, Hua J, Cao X, Wang H . Gelatin induces trophectoderm differentiation of mouse embryonic stem cells. Cell Biol Int 2010; 35: 587–591.

    Article  Google Scholar 

  77. Gyuris J, Golemis E, Chertkov H, Brent R . Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2. Cell 1993; 75: 791–803.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

SVP, NB and CL were supported by NIH grants (CA120352 and CA08093) to SVP, and institutional support from the University of Virginia and the Department of Pathology Mass Spectrometry Facility. AEW is supported by the Swedish Research Council. We would like to thank Janet Cross and Benjamin Purow at UVA for helpful discussions and critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    N Brimer, C Lyons & S B Vande Pol

  2. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    A E Wallberg

Authors
  1. N Brimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A E Wallberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S B Vande Pol
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S B Vande Pol.

Ethics declarations

Competing interests

Dr Vande Pol's work has been funded by the NIH. The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brimer, N., Lyons, C., Wallberg, A. et al. Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling. Oncogene 31, 4639–4646 (2012). https://doi.org/10.1038/onc.2011.589

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.589

Keywords

This article is cited by

Search

Advanced search

Quick links