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Scribble acts as an oncogene in Eμ-myc-driven lymphoma

Oncogene volume 35, pages 1193–1197 (2016)Cite this article

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Abstract

Scribble complex proteins maintain apicobasal polarity, regulate cell fate determination and function as tumour suppressors in epithelial tissue. Despite evidence that the function of Scribble is maintained in the lymphocyte lineage, we still understand little about its role as a tumour suppressor in haematological malignancies. Using the Eμ-myc model of Burkitt’s lymphoma we investigated the role of Scribble in lymphomagenesis. We found that contrary to its well-documented tumour suppressor role in epithelial tissue, loss of Scribble expression delayed the expansion of peripheral B cells and delayed the onset of Eμ-myc-driven lymphoma. This was despite upregulated ERK phosphorylation levels in Scribble-deficient tumours, which are associated with loss of Scribble expression and the development of more aggressive Burkitt’s lymphoma. Interestingly, the developmental stage of lymphoma was unaffected by Scribble expression challenging any role for Scribble in fate determination in the haematopoetic lineage. These data provide evidence for oncogenic properties of Scribble in Myc-driven B-cell lymphomagenesis, reinforcing recent findings that overexpression of a mutant form of Scribble can act as an oncogene in epithelial cells. Our results support the growing appreciation that the tumour regulatory functions of Scribble, and other polarity protein family members, are context dependent.

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References

  1. Mechler BM, McGinnis W, Gehring WJ . Molecular cloning of lethal(2)giant larvae, a recessive oncogene of Drosophila melanogaster. EMBO J 1985; 4: 1551–1557.

    Article  CAS  Google Scholar 

  2. Woods DF, Bryant PJ . Molecular cloning of the lethal(1)discs large-1 oncogene of Drosophila. Dev Biol 1989; 134: 222–235.

    Article  CAS  Google Scholar 

  3. Bilder D, Perrimon N . Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature 2000; 403: 676–680.

    Article  CAS  Google Scholar 

  4. Gardiol D, Zacchi A, Petrera F, Stanta G, Banks L . Human discs large and scrib are localized at the same regions in colon mucosa and changes in their expression patterns are correlated with loss of tissue architecture during malignant progression. Int J Cancer 2006; 119: 1285–1290.

    Article  CAS  Google Scholar 

  5. Kamei Y, Kito K, Takeuchi T, Imai Y, Murase R, Ueda N et al. Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin. Hum Pathol 2007; 38: 1273–1281.

    Article  CAS  Google Scholar 

  6. Vaira V, Faversani A, Dohi T, Montorsi M, Augello C, Gatti S et al. miR-296 regulation of a cell polarity-cell plasticity module controls tumor progression. Oncogene 2012; 31: 27–38.

    Article  CAS  Google Scholar 

  7. Anastas JN, Biechele TL, Robitaille M, Muster J, Allison KH, Angers S et al. A protein complex of SCRIB, NOS1AP and VANGL1 regulates cell polarity and migration, and is associated with breast cancer progression. Oncogene 2012; 31: 3696–3708.

    Article  CAS  Google Scholar 

  8. Zhan L, Rosenberg A, Bergami KC, Yu M, Xuan Z, Jaffe AB et al. Deregulation of scribble promotes mammary tumorigenesis and reveals a role for cell polarity in carcinoma. Cell 2008; 135: 865–878.

    Article  CAS  Google Scholar 

  9. Pearson HB, Perez-Mancera PA, Dow LE, Ryan A, Tennstedt P, Bogani D et al. SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia. J Clin Invest 2011; 121: 4257–4267.

    Article  CAS  Google Scholar 

  10. Elsum IA, Martin C, Humbert PO . Scribble regulates an EMT polarity pathway through modulation of MAPK-ERK signaling to mediate junction formation. J Cell Sci 2013; 126: 3990–3999.

    Article  CAS  Google Scholar 

  11. Ludford-Menting MJ, Oliaro J, Sacirbegovic F, Cheah ET, Pedersen N, Thomas SJ et al. A network of PDZ-containing proteins regulates T cell polarity and morphology during migration and immunological synapse formation. Immunity 2005; 22: 737–748.

    Article  CAS  Google Scholar 

  12. Pike KA, Kulkarni S, Pawson T . Immature T-cell clustering and efficient differentiation require the polarity protein Scribble. Proc Natl Acad Sci USA 2011; 108: 1116–1121.

    Article  CAS  Google Scholar 

  13. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A et al. Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 2007; 315: 1687–1691.

    Article  CAS  Google Scholar 

  14. Oliaro J, Van Ham V, Sacirbegovic F, Pasam A, Bomzon Z, Pham K et al. Asymmetric cell division of T cells upon antigen presentation uses multiple conserved mechanisms. J Immunol 2010; 185: 367–375.

    Article  CAS  Google Scholar 

  15. Zarbalis K, May SR, Shen Y, Ekker M, Rubenstein JL, Peterson AS . A focused and efficient genetic screening strategy in the mouse: identification of mutations that disrupt cortical development. PLoS Biol 2004; 2: E219.

    Article  Google Scholar 

  16. Montcouquiol M, Rachel RA, Lanford PJ, Copeland NG, Jenkins NA, Kelley MW . Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 2003; 423: 173–177.

    Article  CAS  Google Scholar 

  17. Montcouquiol M, Sans N, Huss D, Kach J, Dickman JD, Forge A et al. Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J Neurosci 2006; 26: 5265–5275.

    Article  CAS  Google Scholar 

  18. Murdoch JN, Henderson DJ, Doudney K, Gaston-Massuet C, Phillips HM, Paternotte C et al. Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. Hum Mol Genet 2003; 12: 87–98.

    Article  CAS  Google Scholar 

  19. Dow LE, Elsum IA, King CL, Kinross KM, Richardson HE, Humbert PO . Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling. Oncogene 2008; 27: 5988–6001.

    Article  CAS  Google Scholar 

  20. Dow LE, Kauffman JS, Caddy J, Zarbalis K, Peterson AS, Jane SM et al. The tumour-suppressor Scribble dictates cell polarity during directed epithelial migration: regulation of Rho GTPase recruitment to the leading edge. Oncogene 2007; 26: 2272–2282.

    Article  CAS  Google Scholar 

  21. Young LC, Hartig N, Munoz-Alegre M, Oses-Prieto JA, Durdu S, Bender S et al. An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth. Mol Cell 2013; 52: 679–692.

    Article  CAS  Google Scholar 

  22. Nagasaka K, Pim D, Massimi P, Thomas M, Tomaic V, Subbaiah VK et al. The cell polarity regulator hScrib controls ERK activation through a KIM site-dependent interaction. Oncogene 2010; 29: 5311–5321.

    Article  CAS  Google Scholar 

  23. Hawkins ED, Russell SM . Upsides and downsides to polarity and asymmetric cell division in leukemia. Oncogene 2008; 27: 7003–7017.

    Article  CAS  Google Scholar 

  24. Alexander WS, Bernard O, Cory S, Adams JM . Lymphomagenesis in E mu-myc transgenic mice can involve ras mutations. Oncogene 1989; 4: 575–581.

    CAS  PubMed  Google Scholar 

  25. Gramling MW, Eischen CM . Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis. Cell Death Differ 2012; 19: 1220–1227.

    Article  CAS  Google Scholar 

  26. Wirtz-Peitz F, Nishimura T, Knoblich JA . Linking cell cycle to asymmetric division: aurora-A phosphorylates the Par complex to regulate Numb localization. Cell 2008; 135: 161–173.

    Article  CAS  Google Scholar 

  27. Albertson R, Doe CQ . Dlg, Scrib and Lgl regulate neuroblast cell size and mitotic spindle asymmetry. Nat Cell Biol 2003; 5: 166–170.

    Article  CAS  Google Scholar 

  28. Betschinger J, Mechtler K, Knoblich JA . The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 2003; 422: 326–330.

    Article  CAS  Google Scholar 

  29. Betschinger J, Mechtler K, Knoblich JA . Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 2006; 124: 1241–1253.

    Article  CAS  Google Scholar 

  30. Caussinus E, Gonzalez C . Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 2005; 37: 1125–1129.

    Article  CAS  Google Scholar 

  31. Lee CY, Robinson KJ, Doe CQ . Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation. Nature 2006; 439: 594–598.

    Article  CAS  Google Scholar 

  32. Ting SB, Deneault E, Hope K, Cellot S, Chagraoui J, Mayotte N et al. Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2. Blood 2012; 119: 2510–2522.

    Article  CAS  Google Scholar 

  33. Powell AE, Shung CY, Saylor KW, Mullendorff KA, Weiss JB, Wong MH . Lessons from development: a role for asymmetric stem cell division in cancer. Stem Cell Res 2010; 4: 3–9.

    Article  CAS  Google Scholar 

  34. Florian MC, Geiger H . Concise review: polarity in stem cells, disease, and aging. Stem Cells 2010; 28: 1623–1629.

    Article  Google Scholar 

  35. Hawkins ED, Oliaro J, Kallies A, Belz GT, Filby A, Hogan T et al. Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity. Nat Commun 2013; 4: 1801.

    Article  Google Scholar 

  36. Humphries LA, Shaffer MH, Sacirbegovic F, Tomassian T, McMahon KA, Humbert PO et al. Characterization of in vivo Dlg1 deletion on T cell development and function. PloS One 2012; 7: e45276.

    Article  CAS  Google Scholar 

  37. Hawkins ED, Oliaro J, Ramsbottom KM, Ting SB, Sacirbegovic F, Harvey M et al. Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia. PloS One 2014; 9: e87376.

    Article  Google Scholar 

  38. Sandoval GJ, Graham DB, Gmyrek GB, Akilesh HM, Fujikawa K, Sammut B et al. Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL. Cancer Immunol Res 2013; 1: 126–137.

    Article  Google Scholar 

  39. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985; 318: 533–538.

    Article  CAS  Google Scholar 

  40. Harris AW, Pinkert CA, Crawford M, Langdon WY, Brinster RL, Adams JM . The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med 1988; 167: 353–371.

    Article  CAS  Google Scholar 

  41. Langdon WY, Harris AW, Cory S, Adams JM . The c-myc oncogene perturbs B lymphocyte development in E-mu-myc transgenic mice. Cell 1986; 47: 11–18.

    Article  CAS  Google Scholar 

  42. Prendergast GC . Mechanisms of apoptosis by c-Myc. Oncogene 1999; 18: 2967–2987.

    Article  CAS  Google Scholar 

  43. Kelly PN, Puthalakath H, Adams JM, Strasser A . Endogenous bcl-2 is not required for the development of Emu-myc-induced B-cell lymphoma. Blood 2007; 109: 4907–4913.

    Article  CAS  Google Scholar 

  44. Feigin ME, Akshinthala SD, Araki K, Rosenberg AZ, Muthuswamy LB, Martin B et al. Mislocalization of the cell polarity protein scribble promotes mammary tumorigenesis and is associated with basal breast cancer. Cancer Res 2014; 74: 3180–3194.

    Article  CAS  Google Scholar 

  45. Godde NJ, Sheridan JM, Smith LK, Pearson HB, Britt KL, Galea RC et al. Scribble modulates the MAPK/Fra1 pathway to disrupt luminal and ductal integrity and suppress tumour formation in the mammary gland. PLoS Genet 2014; 10: e1004323.

    Article  Google Scholar 

  46. Iden S, van Riel WE, Schafer R, Song JY, Hirose T, Ohno S et al. Tumor type-dependent function of the par3 polarity protein in skin tumorigenesis. Cancer Cell 2012; 22: 389–403.

    Article  CAS  Google Scholar 

  47. Zen K, Yasui K, Gen Y, Dohi O, Wakabayashi N, Mitsufuji S et al. Defective expression of polarity protein PAR-3 gene (PARD3) in esophageal squamous cell carcinoma. Oncogene 2009; 28: 2910–2918.

    Article  CAS  Google Scholar 

  48. Ellenbroek SI, Iden S, Collard JG . Cell polarity proteins and cancer. Semin Cancer Biol 2012; 22: 208–215.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was funded by the Australian National Health and Medical Research Council (NHRMC, project grants and fellowships to EDH, JO, SMR, POH, RWJ), the Human Frontiers Science Program, the Australian Research Council (ARC, fellowship to SMR) and the Australian Cancer Research Foundation (ACRF, ACRF Cell Biology Program).

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Author notes

  1. E D Hawkins

    Present address: 9Current address: Imperial College London, Sir Alexander Fleming Building, SW72AZ, London, UK.,

Authors and Affiliations

  1. Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    E D Hawkins, J Oliaro, K M Ramsbottom, A Newbold, R W Johnstone & S M Russell

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia,

    E D Hawkins, J Oliaro, K M Ramsbottom, A Newbold, P O Humbert, R W Johnstone & S M Russell

  3. Cancer Therapeutics Programs, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    A Newbold & R W Johnstone

  4. Cell Cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    P O Humbert

  5. Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia,

    P O Humbert

  6. Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, Victoria, Australia

    P O Humbert

  7. Cell cycle and Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    P O Humbert

  8. Centre for Micro-Photonics, Swinburne University of Technology, Hawthorn, Victoria, Australia

    S M Russell

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Hawkins, E., Oliaro, J., Ramsbottom, K. et al. Scribble acts as an oncogene in Eμ-myc-driven lymphoma. Oncogene 35, 1193–1197 (2016). https://doi.org/10.1038/onc.2015.167

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