JNK Regulation of Oncogenesis

  • Heasley, Lynn E. (Department of Medicine, University of Colorado Health Sciences Center) ;
  • Han, Sun-Young (School of Life Sciences and Biotechnology, Korea University)
  • Received : 2006.03.28
  • Accepted : 2006.03.31
  • Published : 2006.04.30


The literature provides strong precedent for both pro-tumorigenic and tumor suppressor roles for the c-Jun N-terminal kinases (JNKs) in the setting of oncogenesis. Clearly, JNKs are activated by numerous oncogenes and growth factors and the literature documents a role for these MAP kinases in cell proliferation and transformation. By contrast, JNKs mediate signals from diverse stimuli that result in cell death or differentiation and a role for JNKs as tumor suppressors has emerged. This enigmatic nature of the JNKs in the setting of oncogenesis is considered herein. Further illumination of the complex and context-dependent functions of the JNKs in cancer cells is of obvious importance for the rational use of small molecule JNK inhibitors as therapeutics.


JNK;MAP Kinase;Tumorigenesis;Transformation;Tumor Suppressor


  1. Bost, F., McKay, R., Bost, M., Potapova, O., Dean, N. M., et al. (1999) The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells. Mol. Cell. Biol. 19, 1938.1949
  2. Brumby, A. M. and Richardson, H. E. (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769.5779 https://doi.org/10.1093/emboj/cdg548
  3. Butterfield, L., Zentrich, E., Beekman, A., and Heasley, L. E. (1999) Stress and cell type-dependent regulation of transfected cJun N-terminal kinase and mitogen-activated protein kinase kinase isoforms. Biochem. J. 338, 681−686 https://doi.org/10.1042/0264-6021:3380681
  4. Engelberg, D. (2004) Stress-activated protein kinases-tumor suppressors or tumor initiators- Semin Cancer Biol. 14, 271-282 https://doi.org/10.1016/j.semcancer.2004.04.006
  5. Farooq, A. and Zhou, M. M. (2004) Structure and regulation of MAPK phosphatases. Cell Signal. 16, 769-779 https://doi.org/10.1016/j.cellsig.2003.12.008
  6. Gonzalez-Garcia, A., Pritchard, C. A., Paterson, H. F., Mavria, G., Stamp, G., et al. (2005) RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219-226 https://doi.org/10.1016/j.ccr.2005.01.029
  7. Hideshima, T., Hayashi, T., Chauhan, D., Akiyama, M., Richardson, P., et al. (2003) Biologic sequelae of c-Jun NH(2)-terminal kinase (JNK) activation in multiple myeloma cell lines. Oncogene 22, 8797-8801 https://doi.org/10.1038/sj.onc.1206919
  8. Hoornaert, I., Marynen, P., Goris, J., Sciot, R., and Baens, M. (2003) MAPK phosphatase DUSP16/MKP-7, a candidate tumor suppressor for chromosome region 12p12-13, reduces BCR-ABL-induced transformation. Oncogene 22, 7728-7736 https://doi.org/10.1038/sj.onc.1207089
  9. Kennedy, N. J., Sluss, H. K., Jones, S. N., Bar-Sagi, D., Flavell, R. A., et al. (2003) Suppression of Ras-stimulated transformation by the JNK signal transduction pathway. Genes Dev. 17, 629-637 https://doi.org/10.1101/gad.1062903
  10. Kim, H. L., Vander Griend, D. J., Yang, X., Benson, D. A., Dubauskas, Z., et al. (2001) Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers. Cancer Res. 61, 2833-2837
  11. Rennefahrt, U. E., Illert, B., Kerkhoff, E., Troppmair, J., and Rapp, U. R. (2002) Constitutive JNK activation in NIH 3T3 fibroblasts induces a partially transformed phenotype. J. Biol. Chem. 277, 29510-29518 https://doi.org/10.1074/jbc.M203010200
  12. Sabapathy, K., Jochumm W., Hochedlinger, K., Chang, L., Karin, M., et al. (1999) Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech. Dev. 89, 115-124 https://doi.org/10.1016/S0925-4773(99)00213-0
  13. Vicent, S., Garayoa, M., Lopez-Picazo, J. M., Lozano, M. D., Toledo, G., et al. (2004) Mitogen-activated protein kinase phosphatase-1 is overexpressed in non-small cell lung cancer and is an independent predictor of outcome in patients. Clin. Cancer Res. 10, 3639-3649 https://doi.org/10.1158/1078-0432.CCR-03-0771
  14. Winn, R. A., Marek, L., Han, S. Y., Rodriguez, K., Rodriguez, N., et al. (2005) Restoration of Wnt-7a expression reverses non-small cell lung cancer cellular transformation through frizzled-9-mediated growth inhibition and promotion of cell differentiation. J. Biol. Chem. 280, 19625-19634 https://doi.org/10.1074/jbc.M409392200
  15. Xia, Y. and Karin, M. (2004) The control of cell motility and epithelial morphogenesis by Jun kinases. Trends Cell Biol. 14, 94-101. https://doi.org/10.1016/j.tcb.2003.12.005
  16. Yang, Y. M., Bost, F., Charbono, W., Dean, N., McKay, R., et al. (2003) C-Jun NH2-terminal kinase mediates proliferation and tumor growth of human prostate carcinoma. Clin. Cancer Res. 9, 391-401
  17. Yoshida, S., Fukino, K., Harada, H., Nagai, H., Imoto, I., et al. (2001) The c-Jun NH2-terminal kinase3 (JNK3) gene: genomic structure, chromosomal assignment, and loss of expression in brain tumors. J. Hum. Genet. 46, 182-187 https://doi.org/10.1007/s100380170086
  18. Theodosiou, A. and Ashworth, A. (2002) MAP kinase phosphatases. Genome Biol. 3, REVIEWS3009
  19. Vasilevskaya, I. and O'Dwyer, P. J. (2003) Role of Jun and Jun kinase in resistance of cancer cells to therapy. Drug Resist. Updat. 6, 147-156 https://doi.org/10.1016/S1368-7646(03)00043-8
  20. Fuchs, S. Y., Fried, V. A., and Ronai, Z. (1998b) Stress-activated kinases regulate protein stability. Oncogene 17, 1483-1490 https://doi.org/10.1038/sj.onc.1202184
  21. Masuda, K., Shima, H., Katagiri, C., and Kikuchi, K. (2003) Activation of ERK induces phosphorylation of MAPK phosphatase- 7, a JNK specific phosphatase, at Ser-446. J. Biol. Chem. 278, 32448-32456 https://doi.org/10.1074/jbc.M213254200
  22. Yamanaka, H., Moriguchi, T., Masuyama, N., Kusakabe, M., Hanafusa, H., et al. (2002) JNK functions in the noncanonical Wnt pathway to regulate convergent extension movements in vertebrates. EMBO Rep. 3, 69-75 https://doi.org/10.1093/embo-reports/kvf008
  23. Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanaugh, J., Sluss, H. K., et al. (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 15, 2760-2770
  24. Kuan, C. Y., Yang, D. D., Samanta Roy, D. R., Davis, R. J., Rakic, P., et al. (1999) The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 22, 667-676 https://doi.org/10.1016/S0896-6273(00)80727-8
  25. Park, H. S., Kim, M. S., Huh, S. H., Park, J., Chung, J., et al. (2002) Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J. Biol. Chem. 277, 2573-2578 https://doi.org/10.1074/jbc.M110299200
  26. Murtagh, J., McArdle, E., Gilligan, E., Thornton, L., Furlong, F., et al. (2004) Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. J. Cell. Biol. 166, 133-143 https://doi.org/10.1083/jcb.200403020
  27. Xu, Y. (2003) Regulation of p53 responses by post-translational modifications. Cell Death Differ. 10, 400-403 https://doi.org/10.1038/sj.cdd.4401182
  28. Han, S. Y., Kim, S. H., and Heasley, L. E. (2002) Differential gene regulation by specific gain-of-function JNK1 proteins expressed in Swiss 3T3 fibroblasts. J. Biol. Chem. 277, 47167-47174
  29. Toh, W. H., Siddique, M. M., Boominathan, L., Lin, K. W., and Sabapathy, K. (2004) c-Jun regulates the stability and activity of the p53 homologue, p73. J. Biol. Chem. 279, 44713-44722 https://doi.org/10.1074/jbc.M407672200
  30. Maesako, Y., Uchiyama, T., and Ohno, H. (2003) Comparison of gene expression profiles of lymphoma cell lines from transformed follicular lymphoma, Burkitt's lymphoma and de novo diffuse large B-cell lymphoma. Cancer Sci. 94, 774-781 https://doi.org/10.1111/j.1349-7006.2003.tb01518.x
  31. Yamada, S. D., Hickson, J. A., Hrobowski, Y., Vander Griend, D. J., Benson, D., et al. (2002) Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer Res. 62, 6717-6723
  32. Buschmann, T., Potapova, O., Bar-Shira, A., Ivanov, V. N., Fuchs, S. Y., et al. (2001) Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress. Mol. Cell. Biol. 21, 2743−2754 https://doi.org/10.1128/MCB.21.8.2743-2754.2001
  33. MacCorkle, R. A. and Tan, T. H. (2004) Inhibition of JNK2 disrupts anaphase and produces aneuploidy in mammalian cells. J. Biol. Chem. 279, 40112-40121 https://doi.org/10.1074/jbc.M405481200
  34. Milne, D. M., Campbell, L. E., Campbell, D. G., and Meek, D. W. (1995) p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1. J. Biol. Chem. 270, 5511-5518 https://doi.org/10.1074/jbc.270.10.5511
  35. Noselli, S. and Agnes, F. (1999) Roles of the JNK signaling pathway in Drosophila morphogenesis. Curr. Opin. Genet. Dev. 9, 466-472 https://doi.org/10.1016/S0959-437X(99)80071-9
  36. Uhlirova, M., Jasper, H., and Bohmann, D. (2005) Non-cellautonomous induction of tissue overgrowth by JNK/Ras cooperation in a Drosophila tumor model. Proc. Natl. Acad. Sci. USA 102, 13123-13128
  37. Wang, H. Y., Cheng, Z., and Malbon, C. C. (2003) Overexpression of mitogen-activated protein kinase phosphatases MKP1, MKP2 in human breast cancer. Cancer Lett. 191, 229-237 https://doi.org/10.1016/S0304-3835(02)00612-2
  38. Mingo-Sion, A. M., Marietta, P. M., Koller, E., Wolf, D. M., and Van Den Berg, C. L. (2004) Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells. Oncogene 23, 596-604 https://doi.org/10.1038/sj.onc.1207147
  39. She, Q. B., Chen, N., Bode, A. M., Flavell, R. A., and Dong, Z. (2002) Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol- 13-acetate. Cancer Res. 62, 1343-1348
  40. Yang, D., Kuan, C.-Y., Whitmarsh, A. J., Rincon, M., Zheng, T. S., et al. (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the JNK3 gene. Nature 389, 865-870 https://doi.org/10.1038/39899
  41. Fuchs, S. Y., Adler, V., Pincus, M. R., and Ronai, Z. (1998a) MEKK1/JNK signaling stabilizes and activates p53. Proc. Natl. Acad. Sci. USA 95, 10541-10546
  42. McEwen, D. G. and Peifer, M. (2005) Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development 132, 3935-3946 https://doi.org/10.1242/dev.01949
  43. Weston, C. R., Wong, A., Hall, J. P., Goad, M. E., Flavell, R. A., et al. (2004) The c-Jun NH2-terminal kinase is essential for epidermal growth factor expression during epidermal morphogenesis. Proc. Natl. Acad. Sci. USA 101, 14114-14119
  44. Kyriakis, J. M. and Avruch, J. (2001) Mammalian mitogenactivated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807-869 https://doi.org/10.1152/physrev.2001.81.2.807
  45. Mialon, A., Sankinen, M., Soderstrom, H., Junttila, T. T., Holmstrom, T., et al. (2005) DNA topoisomerase I is a cofactor for c-Jun in the regulation of epidermal growth factor receptor expression and cancer cell proliferation. Mol. Cell. Biol. 25, 5040-5051 https://doi.org/10.1128/MCB.25.12.5040-5051.2005
  46. Okubo, Y., Blakesley, V. A., Stannard, B., Gutkind, S., and Le Roith, D. (1998) Insulin-like growth factor-1 inhibits the stress-activated protein kinase/c-Jun N-terminal kinase. J. Biol. Chem. 273, 25961-25966 https://doi.org/10.1074/jbc.273.40.25961
  47. Smeal, T., Binetruy, B., Mercola, D. A., Birrer, M., and Karin, M. (1991) Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 354, 494-496 https://doi.org/10.1038/354494a0
  48. Behrens, A., Jochum, W., Sibilia, M., and Wagner, E. F. (2000) Oncogenic transformation by ras and fos is mediated by c- Jun N-terminal phosphorylation. Oncogene 19, 2657.2663 https://doi.org/10.1038/sj.onc.1203603
  49. Eferl, R. and Wagner, E. F. (2003) AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859-868 https://doi.org/10.1038/nrc1209
  50. Martin, P. and Parkhurst, S. M. (2004) Parallels between tissue repair and embryo morphogenesis. Development 131, 3021-3034 https://doi.org/10.1242/dev.01253
  51. Srinivas, H., Juroske, D. M., Kalyankrishna, S., Cody, D. D., Price, R. E., et al. (2005) c-Jun N-terminal kinase contributes to aberrant retinoid signaling in lung cancer cells by phosphorylating and inducing proteasomal degradation of retinoic acid receptor alpha. Mol. Cell. Biol. 25, 1054-1069 https://doi.org/10.1128/MCB.25.3.1054-1069.2005
  52. Wallingford, J. B., Fraser, S. E., and Harland, R. M. (2002) Convergent extension: the molecular control of polarized cell movement during embryonic development. Dev. Cell. 2, 695-706 https://doi.org/10.1016/S1534-5807(02)00197-1
  53. Cerezo, A., Martinez-A, C., Lanzarot, D., Fischer, S., Franke, T. F., et al. (1998) Role of Akt and c-Jun N-terminal kinase 2 in apoptosis induced by interleukin-4 deprivation. Mol. Biol. Cell 8, 3107−3118
  54. Chen, N., Nomura, M., She, Q. B., Ma, W. Y., Bode, A. M., et al. (2001) Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice. Cancer Res. 61, 3908-3912
  55. Nelson, W. J. and Nusse, R. (2004) Convergence of Wnt, betacatenin, and cadherin pathways. Science 303, 1483-1487 https://doi.org/10.1126/science.1094291
  56. Smeal, T., Binetruy, B., Mercola, D., Grover-Bardwick, A., Heidecker, G., et al. (1992) Oncoprotein-mediated signalling cascade stimulates c-Jun activity by phosphorylation of serines 63 and 73. Mol. Cell. Biol. 12, 3507-3513 https://doi.org/10.1128/MCB.12.8.3507
  57. Yamagata, H., Matsuzaki, K., Mori, S., Yoshida, K., Tahashi, Y., et al. (2005) Acceleration of Smad2 and Smad3 phosphorylation via c-Jun NH(2)-terminal kinase during human colorectal carcinogenesis. Cancer Res. 65, 157-165
  58. Gioeli, D., Black, B. E., Gordon, V., Spencer, A., Kesler, C. T., et al. (2006) Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol. Endocrinol. 20, 503-515 https://doi.org/10.1210/me.2005-0351
  59. Nateri, A. S., Spencer-Dene, B., and Behrens, A. (2005) Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature 437, 281-285 https://doi.org/10.1038/nature03914
  60. Vander Griend, D. J., Kocherginsky, M., Hickson, J. A., Stadler, W. M., Lin, A., et al. (2005) Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer Res. 65, 10984-10991 https://doi.org/10.1158/0008-5472.CAN-05-2382
  61. Derijard, B., Hibi, M., Wu, I.-H., Barrett, T., Su, B., et al. (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025-1037 https://doi.org/10.1016/0092-8674(94)90380-8
  62. Lowe, S. W., Cepero, E., and Evan, G. (2004) Intrinsic tumour suppression. Nature 432, 307-315 https://doi.org/10.1038/nature03098
  63. Manning, A. M. and Davis, R. J. (2003) Targeting JNK for therapeutic benefit: from junk to gold- Nat. Rev. Drug Discov. 2, 554-565 https://doi.org/10.1038/nrd1132
  64. Hess, P., Pihan, G., Sawyers, C. L., Flavell, R. A., and Davis, R. J. (2002) Survival signaling mediated by c-Jun NH(2)-terminal kinase in transformed B lymphoblasts. Nat. Genet. 32, 201-205 https://doi.org/10.1038/ng946
  65. Johnson, G. L. and Lapadat, R. (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912 https://doi.org/10.1126/science.1072682
  66. Brumby, A. M. and Richardson, H. E. (2005) Using Drosophila melanogaster to map human cancer pathways. Nat. Rev. Cancer 5, 626−639 https://doi.org/10.1038/nrc1671
  67. Yoshida, B. A., Dubauskas, Z., Chekmareva, M. A., Christiano, T. R., Stadler, W. M., et al. (1999) Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res. 59, 5483-5487
  68. Eferl, R., Ricci, R., Kenner, L., Zenz, R., David, J. P., et al. (2003) Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 112, 181-192 https://doi.org/10.1016/S0092-8674(03)00042-4
  69. Levresse, V., Butterfield, L., Zentrich, E., and Heasley, L. E. (2000) Akt negatively regulates the cJun N-terminal kinase pathway in PC12 cells. J. Neurosci. Res. 62, 799-808 https://doi.org/10.1002/1097-4547(20001215)62:6<799::AID-JNR6>3.0.CO;2-1
  70. Veeman, M. T., Axelrod, J. D., and Moon, R. T. (2003) A second canon. Functions and mechanisms of beta-cateninindependent Wnt signaling. Dev. Cell 5, 367-377 https://doi.org/10.1016/S1534-5807(03)00266-1