, Volume 22, Issue 4, pp 479–490 | Cite as

Myc inhibits JNK-mediated cell death in vivo



The proto-oncogene Myc is well known for its roles in promoting cell growth, proliferation and apoptosis. However, in this study, we found from a genetic screen that Myc inhibits, rather than promotes, cell death triggered by c-Jun N-terminal kinase (JNK) signaling in Drosophila. Firstly, expression of Drosophila Myc (dMyc) suppresses, whereas loss of dMyc enhances, ectopically activated JNK signaling-induced cell death. Secondly, dMyc impedes physiologically activated JNK pathway-mediated cell death. Thirdly, loss of dMyc triggers JNK pathway activation and JNK-dependent cell death. Finally, the mammalian cMyc gene, when expressed in Drosophila, impedes activated JNK signaling-induced cell death. Thus, besides its well-studied apoptosis promoting function, Myc also antagonizes JNK-mediated cell death in Drosophila, and this function is likely conserved from fly to human.


JNK pathway Myc Cell death Drosophila 

Supplementary material

10495_2016_1340_MOESM1_ESM.pdf (821 kb)
Supplementary material 1 (PDF 821 KB)


  1. 1.
    Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4):742–758. doi:10.1016/j.cell.2011.10.033 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Saeed WK, Jun DW (2014) Necroptosis: an emerging type of cell death in liver diseases. World J Gastroenterol 20(35):12526–12532. doi:10.3748/wjg.v20.i35.12526 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Viry E, Paggetti J, Baginska J, Mgrditchian T, Berchem G, Moussay E, Janji B (2014) Autophagy: an adaptive metabolic response to stress shaping the antitumor immunity. Biochem Pharmacol 92(1):31–42. doi:10.1016/j.bcp.2014.07.006 CrossRefPubMedGoogle Scholar
  4. 4.
    Conradt B (2009) Genetic control of programmed cell death during animal development. Annu Rev Genet 43:493–523. doi:10.1146/annurev.genet.42.110807.091533 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Enomoto M, Vaughen J, Igaki T (2015) Non-autonomous overgrowth by oncogenic niche cells: cellular cooperation and competition in tumorigenesis. Cancer Sci 106(12):1651–1658. doi:10.1111/cas.12816 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Johnston LA (2014) Socializing with MYC: cell competition in development and as a model for premalignant cancer. Cold Spring Harb Perspect Med 4(4):a014274. doi:10.1101/cshperspect.a014274 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802(4):396–405. doi:10.1016/j.bbadis.2009.12.009 CrossRefPubMedGoogle Scholar
  8. 8.
    Grifoni D, Bellosta P (2015) Drosophila Myc: a master regulator of cellular performance. Biochim Biophys Acta 1849(5):570–581. doi:10.1016/j.bbagrm.2014.06.021 CrossRefPubMedGoogle Scholar
  9. 9.
    Grewal SS, Li L, Orian A, Eisenman RN, Edgar BA (2005) Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nat Cell Biol 7(3):295–302. doi:10.1038/ncb1223 CrossRefPubMedGoogle Scholar
  10. 10.
    Qiu B, Simon MC (2015) Oncogenes strike a balance between cellular growth and homeostasis. Semin Cell Dev Biol 43:3–10. doi:10.1016/j.semcdb.2015.08.005 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA (2004) Drosophila myc regulates organ size by inducing cell competition. Cell 117(1):107–116CrossRefPubMedGoogle Scholar
  12. 12.
    Gallant P (2013) Myc function in Drosophila. Cold Spring Harb Perspect Med 3(10):a014324. doi:10.1101/cshperspect.a014324 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Moreno E, Basler K (2004) dMyc transforms cells into super-competitors. Cell 117(1):117–129CrossRefPubMedGoogle Scholar
  14. 14.
    de la Cova C, Senoo-Matsuda N, Ziosi M, Wu DC, Bellosta P, Quinzii CM, Johnston LA (2014) Supercompetitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. Cell Metab 19(3):470–483. doi:10.1016/j.cmet.2014.01.012 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    McMahon SB (2014) MYC and the control of apoptosis. Cold Spring Harb Perspect Med 4 (7):a014407. doi:10.1101/cshperspect.a014407 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zhang C, Casas-Tinto S, Li G, Lin N, Chung M, Moreno E, Moberg KH, Zhou L (2015) An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia. Oncogene 34(18):2385–2397. doi:10.1038/onc.2014.160 CrossRefPubMedGoogle Scholar
  17. 17.
    Benassayag C, Montero L, Colombie N, Gallant P, Cribbs D, Morello D (2005) Human c-Myc isoforms differentially regulate cell growth and apoptosis in Drosophila melanogaster. Mol Cell Biol 25(22):9897–9909. doi:10.1128/MCB.25.22.9897-9909.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Walczynski J, Lyons S, Jones N, Breitwieser W (2014) Sensitisation of c-MYC-induced B-lymphoma cells to apoptosis by ATF2. Oncogene 33(8):1027–1036. doi:10.1038/onc.2013.28 CrossRefPubMedGoogle Scholar
  19. 19.
    Conacci-Sorrell M, Ngouenet C, Anderson S, Brabletz T, Eisenman RN (2014) Stress-induced cleavage of Myc promotes cancer cell survival. Gene Dev 28(7):689–707. doi:10.1101/gad.231894.113 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Conacci-Sorrell M, Ngouenet C, Eisenman RN (2010) Myc-Nick: a cytoplasmic cleavage product of Myc that promotes alpha-tubulin acetylation and cell differentiation. Cell 142(3):480–493. doi:10.1016/j.cell.2010.06.037 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Weston CR, Davis RJ (2007) The JNK signal transduction pathway. Curr Opin Cell Biol 19(2):142–149. doi:10.1016/j.ceb.2007.02.001 CrossRefPubMedGoogle Scholar
  22. 22.
    Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27(48):6245–6251. doi:10.1038/onc.2008.301 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410(6824):37–40. doi:10.1038/35065000 CrossRefPubMedGoogle Scholar
  24. 24.
    Igaki T, Miura M (2014) The Drosophila TNF ortholog Eiger: emerging physiological roles and evolution of the TNF system. Semin Immunol 26(3):267–274. doi:10.1016/j.smim.2014.05.003 CrossRefPubMedGoogle Scholar
  25. 25.
    Manieri E, Sabio G (2015) Stress kinases in the modulation of metabolism and energy balance. J Mol Endocrinol 55(2):R11–R22. doi:10.1530/JME-15-0146 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moreno E, Yan MH, Basler K (2002) Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol 12(14):1263–1268. doi:10.1016/S0960-9822(02)00954-5 CrossRefPubMedGoogle Scholar
  27. 27.
    Igaki T, Kanda H, Yamamoto-Goto Y, Kanuka H, Kuranaga E, Aigaki T, Miura M (2002) Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. Embo J 21(12):3009–3018. doi:10.1093/emboj/cdf306 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Rothlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, Leopold P (2015) The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. Nature 522(7557):482–486. doi:10.1038/nature14298 CrossRefPubMedGoogle Scholar
  29. 29.
    Takatsu Y, Nakamura M, Stapleton M, Danos MC, Matsumoto K, O’Connor MB, Shibuya H, Ueno N (2000) TAK1 participates in c-Jun N-terminal kinase signaling during Drosophila development. Mol Cell Biol 20(9):3015–3026CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Glise B, Bourbon H, Noselli S (1995) hemipterous encodes a novel Drosophila MAP kinase kinase, required for epithelial cell sheet movement. Cell 83(3):451–461CrossRefPubMedGoogle Scholar
  31. 31.
    Martin-Blanco E (1997) Regulation of cell differentiation by the Drosophila Jun kinase cascade. Curr Opin Genet Dev 7(5):666–671CrossRefPubMedGoogle Scholar
  32. 32.
    Moreno E, Yan M, Basler K (2002) Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr Biol 12(14):1263–1268CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang S, Chen C, Wu C, Yang Y, Li W, Xue L (2015) The canonical Wg signaling modulates Bsk-mediated cell death in Drosophila. Cell Death Dis 6:e1713. doi:10.1038/cddis.2015.85 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wu CX, Chen YJ, Wang F, Chen CY, Zhang SP, Li CJ, Li WZ, Wu SA, Xue L (2015) Pelle modulates dFoxO-mediated cell death in Drosophila. PLoS Genet 11(10):e1005589.doi:10.1371/journal.pgen.1005589 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang XJ, Ma YQ, Zhao Y, Chen YJ, Hu YJ, Chen CY, Shao YY, Xue L (2015) APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis 20(6):778–786. doi:10.1007/s10495-015-1097-1 CrossRefPubMedGoogle Scholar
  36. 36.
    Ma XJ, Chen YJ, Xu WY, Wu NN, Li MQ, Cao Y, Wu S, Li QT, Xue L (2015) Impaired Hippo signaling promotes Rho1-JNK-dependent growth. P Natl Acad Sci USA 112(4):1065–1070. doi:10.1073/pnas.1415020112 CrossRefGoogle Scholar
  37. 37.
    Huang J, Xue L (2015) Loss of flfl Triggers JNK-Dependent Cell Death in Drosophila. BioMed Res Int 2015:623573. doi:10.1155/2015/623573 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Ma X, Li W, Yu H, Yang Y, Li M, Xue L, Xu T (2014) Bendless modulates JNK-mediated cell death and migration in Drosophila. Cell Death Differ 21(3):407–415. doi:10.1038/cdd.2013.154 CrossRefPubMedGoogle Scholar
  39. 39.
    Ma X, Yang L, Yang Y, Li M, Li W, Xue L (2013) dUev1a modulates TNF-JNK mediated tumor progression and cell death in Drosophila. Dev Biol 380(2):211–221CrossRefPubMedGoogle Scholar
  40. 40.
    Ma X, Shao Y, Zheng H, Li M, Li W, Xue L (2013) Src42A modulates tumor invasion and cell death via Ben/dUev1a-mediated JNK activation in Drosophila. Cell Death Dis 4:e864. doi:10.1038/cddis.2013.392 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Ma X, Huang J, Yang L, Yang Y, Li W, Xue L (2012) NOPO modulates Egr-induced JNK-independent cell death in Drosophila. Cell Res 22(2):425–431. doi:10.1038/cr.2011.135 CrossRefPubMedGoogle Scholar
  42. 42.
    Xue L, Igaki T, Kuranaga E, Kanda H, Miura M, Xu T (2007) Tumor suppressor CYLD regulates JNK-Induced cell death in Drosophila. Dev Cell 13(3):446–454. doi:10.1016/j.devcel.2007.07.012 CrossRefPubMedGoogle Scholar
  43. 43.
    Geuking P, Narasimamurthy R, Basler K (2005) A genetic screen targeting the tumor necrosis factor/Eiger signaling pathway: identification of Drosophila TAB2 as a functionally conserved component. Genetics 171(4):1683–1694. doi:10.1534/genetics.105.045534 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Geuking P, Narasimamurthy R, Lemaitre B, Basler K, Leulier F (2009) A non-redundant role for Drosophila Mkk4 and hemipterous/Mkk7 in TAK1-mediated activation of JNK. PLoS ONE 4(11):e7709. doi:10.1371/journal.pone.0007709 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhang S, Guo X, Chen C, Chen Y, Li J, Sun Y, Wu C, Yang Y, Jiang C, Li W, Xue L (2016) dFoxO promotes Wingless signaling in Drosophila. Sci Rep 6:22348. doi:10.1038/srep22348 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ma X, Xu W, Zhang D, Yang Y, Li W, Xue L (2015) Wallenda regulates JNK-mediated cell death in Drosophila. Cell Death Dis 6:e1737. doi:10.1038/cddis.2015.111 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hu Y, Han Y, Shao Y, Wang X, Ma Y, Ling E, Xue L (2015) Gr33a modulates Drosophila male courtship preference. Sci Rep 5:7777. doi:10.1038/srep07777 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Bourbon HM, Gonzy-Treboul G, Peronnet F, Alin MF, Ardourel C, Benassayag C, Cribbs D, Deutsch J, Ferrer P, Haenlin M, Lepesant JA, Noselli S, Vincent A (2002) A P-insertion screen identifying novel X-linked essential genes in Drosophila. Mech Dev 110(1–2):71–83CrossRefPubMedGoogle Scholar
  49. 49.
    Xue L, Noll M (2002) Dual role of the Pax gene paired in accessory gland development of Drosophila Development 129(2):339–346PubMedGoogle Scholar
  50. 50.
    Baud V, Karin M (2001) Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 11(9):372–377 pii]CrossRefPubMedGoogle Scholar
  51. 51.
    Wu C, Chen C, Dai J, Zhang F, Chen Y, Li W, Pastor-Pareja JC, Xue L (2015) Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila. Open Biol 5(7):140171. doi:10.1098/rsob.140171 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Montero L, Muller N, Gallant P (2008) Induction of apoptosis by Drosophila Myc. Genesis 46(2):104–111. doi:10.1002/dvg.20373 CrossRefPubMedGoogle Scholar
  53. 53.
    Martin-Blanco E, Gampel A, Ring J, Virdee K, Kirov N, Tolkovsky AM, Martinez-Arias A (1998) Puckered encodes a phosphatase that mediates a feedback loop regulating JNK activity during dorsal closure in Drosophila. Gene Dev 12(4):557–570CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Agnes F, Suzanne M, Noselli S (1999) The Drosophila JNK pathway controls the morphogenesis of imaginal discs during metamorphosis. Development 126(23):5453–5462PubMedGoogle Scholar
  55. 55.
    Gallant P, Shiio Y, Cheng PF, Parkhurst SM, Eisenman RN (1996) Myc and max homologs in Drosophila. Science 274(5292):1523–1527. doi:10.1126/science.274.5292.1523 CrossRefPubMedGoogle Scholar
  56. 56.
    Rohban S, Campaner S (2015) Myc induced replicative stress response: how to cope with it and exploit it. Biochim Biophys Acta 1849(5):517–524. doi:10.1016/j.bbagrm.2014.04.008 CrossRefPubMedGoogle Scholar
  57. 57.
    Wang Q, Zhang Y, Yang HS (2012) Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. Biochim Biophys Acta 1823(10):1807–1814. doi:10.1016/j.bbamcr.2012.07.004 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Noguchi K, Kitanaka C, Yamana H, Kokubu A, Mochizuki T, Kuchino Y (1999) Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J Biol Chem 274(46):32580–32587CrossRefPubMedGoogle Scholar
  59. 59.
    Alarcon-Vargas D, Ronai Ze (2004) c-Jun-NH2 kinase (JNK) contributes to the regulation of c-Myc protein stability. J Biol Chem 279(6):5008–5016CrossRefPubMedGoogle Scholar
  60. 60.
    Zhao Q, Assimopoulou AN, Klauck SM, Damianakos H, Chinou I, Kretschmer N, Rios JL, Papageorgiou VP, Bauer R, Efferth T (2015) Inhibition of c-MYC with involvement of ERK/JNK/MAPK and AKT pathways as a novel mechanism for shikonin and its derivatives in killing leukemia cells. Oncotarget 6(36):38934–38951. doi:10.18632/oncotarget.5380 PubMedPubMedCentralGoogle Scholar
  61. 61.
    Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, Williams E, Loo LW, Cowley SM, Yost C, Pierce S, Edgar BA, Parkhurst SM, Eisenman RN (2003) Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev 17(9):1101–1114. doi:10.1101/gad.1066903 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Spotts GD, Patel SV, Xiao Q, Hann SR (1997) Identification of downstream-initiated c-Myc proteins which are dominant-negative inhibitors of transactivation by full-length c-Myc proteins. Mol Cell Biol 17(3):1459–1468CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Hann SR (1995) Methionine deprivation regulates the translation of functionally-distinct c-Myc proteins. Adv Exp Med Biol 375:107–116CrossRefPubMedGoogle Scholar
  64. 64.
    Dang CV (2012) MYC on the path to cancer. Cell 149(1):22–35. doi:10.1016/j.cell.2012.03.003 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI (2008) Modelling Myc inhibition as a cancer therapy. Nature 455(7213):679–683. doi:10.1038/nature07260 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Institute of Intervention Vessel, Shanghai 10th People’s Hospital, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and TechnologyTongji UniversityShanghaiChina

Personalised recommendations