Publikationsserver der Universitätsbibliothek Marburg
Titel:Immunfluoreszenz-Basierte Hochdurchsatzanalyse Identifiziert MK5 als Myc-Regulierende Kinase
Autor:Kreß, Theresia
Weitere Beteiligte: Lingelbach, Klaus (Prof. Dr.)
Veröffentlicht:2011
URI:https://archiv.ub.uni-marburg.de/diss/z2011/0105
DOI: https://doi.org/10.17192/z2011.0105
URN: urn:nbn:de:hebis:04-z2011-01051
DDC: Biowissenschaften, Biologie
Titel (trans.):Immunofluorescence-Based High Throughput Analysis Identifies MK5 as Myc-Regulating Kinase
Publikationsdatum:2011-06-28
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Myc, Posttranskriptionelle Regulation, miRNS, MK5, MK5, Darmkrebs, FoxO, FoxO

Zusammenfassung:
Der Transkriptionsfaktor Myc spielt eine entscheidende Rolle bei der Tumorentstehung und dem Tumorwachstum. Dabei ist das MYC-Gen in humanen Tumoren selten mutiert, sondern häufig sind Mechanismen der post-transkriptionellen Regulation der Myc- Proteinexpression verändert. Zur Identifikation unbeschriebener Mechanismen der Regulation der Myc-Proteinexpression wurde ein Immunfluoreszenz-basiertes Hochdurchsatzanalyse-Verfahren entwickelt und etabliert. Die Hochdurchsatzanalyse von RNAi-Bibliotheken, die das humane Kinom als Zielproteine auswiesen, identifizierte die Proteinkinase MK5/MAPKAPK5/PRAK als ein Enzym, das die Myc-Proteinexpression negativ reguliert. Die MK5-Depletion führt zu einer erhöhten Myc-Proteinexpression, während die MK5-Überexpression die Myc-Proteinexpression vermindert. Diese Myc- Regulation ist entscheidend am Zellwachstum von Tumorzelllinien beteiligt. MK5 phosphoryliert den Transkriptionsfaktor FoxO3a an mehreren, teilweise evolutionär hoch-konservierten Serin-Resten: S215, S253, S551, S555. Die Phosphorylierung von S215 wurde in vivo bestätigt und trägt wesentlich zur nukleären FoxO3a-Akkumulation bei. Nach Aktivierung durch MK5 bindet FoxO3a direkt an den Promotor der microRNAs miR-34b/c und induziert deren Expression. miR-34b und miR-34c binden an das 3’-UTR der MYC-mRNA und hemmen deren Translation und somit die Myc-Proteinexpression. Bei MK5 handelt es sich um ein aktiviertes Zielgen des Myc-Transkriptionsfaktors, der direkt an die E-Box-Region innerhalb des MK5-Promotors bindet. Hierdurch ergibt sich ein negativer Rückkopplungsmechanismus bestehend aus Myc, MK5, FoxO3a und miR-34b/c. Dieser negative Rückkopplungsmechanismus spielt eine entscheidende Rolle bei der Kolonkarzinogenese. Beim Übergang vom gut- zum schlecht-differenzierten kolorektalen Adenokarzinom wird die MK5-mRNA- und Proteinexpression vermindert. Hierdurch erhöht sich die Myc-Proteinexpression, was zur Tumorprogression und zur Metastasierung führt.

Bibliographie / References

  1. Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685.
  2. Lehtinen, M. K., Yuan, Z., Boag, P. R., Yang, Y., Villen, J., Becker, E. B., DiBacco, S., de la Iglesia, N., Gygi, S., Blackwell, T. K., and Bonni, A. (2006). A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125, 987-1001.
  3. Hu, M. C., Lee, D. F., Xia, W., Golfman, L. S., Ou-Yang, F., Yang, J. Y., Zou, Y., Bao, S., Hanada, N., Saso, H., et al. (2004). IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225-237.
  4. Hann, S. R., Abrams, H. D., Rohrschneider, L. R., and Eisenman, R. N. (1983). Proteins encoded by v-myc and c-myc oncogenes: identification and localization in acute leukemia virus transformants and bursal lymphoma cell lines. Cell 34, 789-798.
  5. Hann, S. R., Thompson, C. B., and Eisenman, R. N. (1985). c-myc oncogene protein synthesis is independent of the cell cycle in human and avian cells. Nature 314, 366-369.
  6. Gomez-Roman, N., Grandori, C., Eisenman, R. N., and White, R. J. (2003). Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290-294.
  7. Welcker, M., Orian, A., Grim, J. E., Eisenman, R. N., and Clurman, B. E. (2004a). A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Curr Biol 14, 1852-1857.
  8. Grandori, C., Gomez-Roman, N., Felton-Edkins, Z. A., Ngouenet, C., Galloway, D. A., Eisenman, R. N., and White, R. J. (2005). c-Myc binds to human ribosomal DNA and stimulates transcription of rRNA genes by RNA polymerase I. Nat Cell Biol 7, 311-318.
  9. Wu, R., Lin, L., Beer, D. G., Ellenson, L. H., Lamb, B. J., Rouillard, J. M., Kuick, R., Hanash, S., Schwartz, D. R., Fearon, E. R., and Cho, K. R. (2003). Amplification and overexpression of the L-MYC proto-oncogene in ovarian carcinomas. Am J Pathol 162, 1603-1610.
  10. Seternes, O. M., Mikalsen, T., Johansen, B., Michaelsen, E., Armstrong, C. G., Morrice, N. A., Turgeon, B., Meloche, S., Moens, U., and Keyse, S. M. (2004). Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J 23, 4780-4791.
  11. Brummelkamp, T. R., Bernards, R., and Agami, R. (2002). Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243-247.
  12. Medema, R. H., Kops, G. J., Bos, J. L., and Burgering, B. M. (2000). AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782-787.
  13. Staller, P., Peukert, K., Kiermaier, A., Seoane, J., Lukas, J., Karsunky, H., Moroy, T., Bartek, J., Massague, J., Hanel, F., and Eilers, M. (2001). Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol 3, 392-399.
  14. Meyer, N., and Penn, L. Z. (2008). Reflecting on 25 years with MYC. Nat Rev Cancer 8, 976-990.
  15. Chang, C. C., Huang, P. S., Lin, H. R., and Lu, C. H. (2007a). Transactivation of protein expression by rice HSP101 in planta and using Hsp101 as a selection marker for transformation. Plant Cell Physiol 48, 1098-1107.
  16. Taub, R., Kirsch, I., Morton, C., Lenoir, G., Swan, D., Tronick, S., Aaronson, S., and Leder, P. (1982). Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A 79, 7837-7841.
  17. Hu, M. C., and Rosenblum, N. D. (2005). Smad1, beta-catenin and Tcf4 associate in a molecular complex with the Myc promoter in dysplastic renal tissue and cooperate to control Myc transcription. Development 132, 215-225.
  18. Schwinkendorf, D., and Gallant, P. (2009). The conserved Myc box 2 and Myc box 3 regions are important, but not essential, for Myc function in vivo. Gene 436, 90-100.
  19. Steiger, D., Furrer, M., Schwinkendorf, D., and Gallant, P. (2008). Max-independent functions of Myc in Drosophila melanogaster. Nat Genet 40, 1084-1091.
  20. Pelengaris, S., Abouna, S., Cheung, L., Ifandi, V., Zervou, S., and Khan, M. (2004). Brief inactivation of c-Myc is not sufficient for sustained regression of c-Myc-induced tumours of pancreatic islets and skin epidermis. BMC Biol 2, 26.
  21. Flores, I., Murphy, D. J., Swigart, L. B., Knies, U., and Evan, G. I. (2004). Defining the temporal requirements for Myc in the progression and maintenance of skin neoplasia. Oncogene 23, 5923-5930.
  22. Tak, H., Jang, E., Kim, S. B., Park, J., Suk, J., Yoon, Y. S., Ahn, J. K., Lee, J. H., and Joe, C. O. (2007). 14-3-3epsilon inhibits MK5-mediated cell migration by disrupting F-actin polymerization. Cell Signal 19, 2379-2387.
  23. Hutvagner, G., and Zamore, P. D. (2002). A microRNA in a multiple-turnover RNAi enzyme complex. Science 297, 2056-2060.
  24. Schumacher, S., Laass, K., Kant, S., Shi, Y., Visel, A., Gruber, A. D., Kotlyarov, A., and Gaestel, M. (2004). Scaffolding by ERK3 regulates MK5 in development. EMBO J 23, 4770-4779.
  25. Zamore, P. D., Tuschl, T., Sharp, P. A., and Bartel, D. P. (2000). RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25-33.
  26. Chan, C. H., Lee, S. W., Li, C. F., Wang, J., Yang, W. L., Wu, C. Y., Wu, J., Nakayama, K. I., Kang, H. Y., Huang, H. Y., et al. (2010). Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 12, 457-467.
  27. Paulin, F. E., West, M. J., Sullivan, N. F., Whitney, R. L., Lyne, L., and Willis, A. E. (1996). Aberrant translational control of the c-myc gene in multiple myeloma. Oncogene 13, 505-513.
  28. Burgering, B. M. (2008). A brief introduction to FOXOlogy. Oncogene 27, 2258-2262.
  29. Iversen, P. W., Eastwood, B. J., Sittampalam, G. S., and Cox, K. L. (2006). A comparison of assay performance measures in screening assays: signal window, Z' factor, and assay variability ratio. J Biomol Screen 11, 247-252.
  30. Hayward, W. S., Neel, B. G., and Astrin, S. M. (1981). Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature 290, 475-480.
  31. Iakova, P., Awad, S. S., and Timchenko, N. A. (2003). Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell 113, 495-506.
  32. Plas, D. R., and Thompson, C. B. (2003). Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278, 12361-12366.
  33. Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., and Greenberg, M. E. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868.
  34. Vogelstein, B., Fearon, E. R., Kern, S. E., Hamilton, S. R., Preisinger, A. C., Nakamura, Y., and White, R. (1989). Allelotype of colorectal carcinomas. Science 244, 207-211.
  35. He, L., He, X., Lim, L. P., de Stanchina, E., Xuan, Z., Liang, Y., Xue, W., Zender, L., Magnus, J., Ridzon, D., et al. (2007). A microRNA component of the p53 tumour suppressor network. Nature 447, 1130-1134.
  36. Ramaswamy, S., Nakamura, N., Sansal, I., Bergeron, L., and Sellers, W. R. (2002). A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2, 81-91.
  37. Moser, A. R., Luongo, C., Gould, K. A., McNeley, M. K., Shoemaker, A. R., and Dove, W. F. (1995). ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J Cancer 31A, 1061-1064.
  38. Paddison, P. J., Silva, J. M., Conklin, D. S., Schlabach, M., Li, M., Aruleba, S., Balija, V., O'Shaughnessy, A., Gnoj, L., Scobie, K., et al. (2004). A resource for large-scale RNA- interference-based screens in mammals. Nature 428, 427-431.
  39. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293, 1146- 1150.
  40. Yeh, E., Cunningham, M., Arnold, H., Chasse, D., Monteith, T., Ivaldi, G., Hahn, W. C., Stukenberg, P. T., Shenolikar, S., Uchida, T., et al. (2004). A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nat Cell Biol 6, 308-318.
  41. Hamilton, A. J., and Baulcombe, D. C. (1999). A species of small antisense RNA in posttranscriptional gene silencing in plants. Science 286, 950-952.
  42. Prendergast, G. C., Lawe, D., and Ziff, E. B. (1991). Association of Myn, the murine homolog of max, with c-Myc stimulates methylation-sensitive DNA binding and ras cotransformation. Cell 65, 395-407.
  43. Seternes, O. M., Johansen, B., Hegge, B., Johannessen, M., Keyse, S. M., and Moens, U. (2002). Both binding and activation of p38 mitogen-activated protein kinase (MAPK) play essential roles in regulation of the nucleocytoplasmic distribution of MAPK-activated protein kinase 5 by cellular stress. Mol Cell Biol 22, 6931-6945.
  44. Underwood, K. W., Parris, K. D., Federico, E., Mosyak, L., Czerwinski, R. M., Shane, T., Taylor, M., Svenson, K., Liu, Y., Hsiao, C. L., et al. (2003). Catalytically active MAP KAP kinase 2 structures in complex with staurosporine and ADP reveal differences with the autoinhibited enzyme. Structure 11, 627-636.
  45. Kelly, K., Cochran, B. H., Stiles, C. D., and Leder, P. (1983). Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell 35, 603- 610.
  46. Kant, S., Schumacher, S., Singh, M. K., Kispert, A., Kotlyarov, A., and Gaestel, M. (2006). Characterization of the atypical MAPK ERK4 and its activation of the MAPK- activated protein kinase MK5. J Biol Chem 281, 35511-35519.
  47. Y., Brodeur, G., and Trent, J. (1984). Chromosome localization in normal human cells and neuroblastomas of a gene related to c-myc. Nature 308, 288-291.
  48. Yano, T., Sander, C. A., Clark, H. M., Dolezal, M. V., Jaffe, E. S., and Raffeld, M. (1993). Clustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma. Oncogene 8, 2741-2748.
  49. Stoneley, M., Paulin, F. E., Le Quesne, J. P., Chappell, S. A., and Willis, A. E. (1998). C- Myc 5' untranslated region contains an internal ribosome entry segment. Oncogene 16, 423-428.
  50. Ioannidis, P., Trangas, T., Dimitriadis, E., Samiotaki, M., Kyriazoglou, I., Tsiapalis, C. M., Kittas, C., Agnantis, N., Nielsen, F. C., Nielsen, J., et al. (2001). C-MYC and IGF-II mRNA-binding protein (CRD-BP/IMP-1) in benign and malignant mesenchymal tumors.
  51. Johansen, L. M., Iwama, A., Lodie, T. A., Sasaki, K., Felsher, D. W., Golub, T. R., and Tenen, D. G. (2001). c-Myc is a critical target for c/EBPalpha in granulopoiesis. Mol Cell Biol 21, 3789-3806.
  52. Clark, K. L., Halay, E. D., Lai, E., and Burley, S. K. (1993). Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature 364, 412-420.
  53. Noubissi, F. K., Elcheva, I., Bhatia, N., Shakoori, A., Ougolkov, A., Liu, J., Minamoto, T., Ross, J., Fuchs, S. Y., and Spiegelman, V. S. (2006). CRD-BP mediates stabilization of betaTrCP1 and c-myc mRNA in response to beta-catenin signalling. Nature 441, 898-901.
  54. Leeds, P., Kren, B. T., Boylan, J. M., Betz, N. A., Steer, C. J., Gruppuso, P. A., and Ross, J. (1997). Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c- myc mRNA in vitro. Oncogene 14, 1279-1286.
  55. Carter, P. S., Jarquin-Pardo, M., and De Benedetti, A. (1999). Differential expression of Myc1 and Myc2 isoforms in cells transformed by eIF4E: evidence for internal ribosome repositioning in the human c-myc 5'UTR. Oncogene 18, 4326-4335.
  56. Roussel, M. F., Davis, J. N., Cleveland, J. L., Ghysdael, J., and Hiebert, S. W. (1994). Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1. Oncogene 9, 405-415.
  57. Chen, C. R., Kang, Y., Siegel, P. M., and Massague, J. (2002). E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression. Cell 110, 19-32.
  58. Vincent, A., Perrais, M., Desseyn, J. L., Aubert, J. P., Pigny, P., and Van Seuningen, I. (2007). Epigenetic regulation (DNA methylation, histone modifications) of the 11p15 mucin genes (MUC2, MUC5AC, MUC5B, MUC6) in epithelial cancer cells. Oncogene 26, 6566-6576.
  59. Toyota, M., Suzuki, H., Sasaki, Y., Maruyama, R., Imai, K., Shinomura, Y., and Tokino, T. (2008). Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. Cancer Res 68, 4123-4132.
  60. Kinsella, T. M., and Nolan, G. P. (1996). Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum Gene Ther 7, 1405-1413.
  61. Yi, R., Qin, Y., Macara, I. G., and Cullen, B. R. (2003). Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev 17, 3011-3016.
  62. Jacobs, F. M., van der Heide, L. P., Wijchers, P. J., Burbach, J. P., Hoekman, M. F., and Smidt, M. P. (2003). FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278, 35959-35967.
  63. Modur, V., Nagarajan, R., Evers, B. M., and Milbrandt, J. (2002). FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem 277, 47928-47937.
  64. Greer, E. L., and Brunet, A. (2008). FOXO transcription factors in ageing and cancer. Acta Physiol (Oxf) 192, 19-28.
  65. Salazar, R., Roepman, P., Capella, G., Moreno, V., Simon, I., Dreezen, C., Lopez-Doriga, A., Santos, C., Marijnen, C., Westerga, J., et al. (2010). Gene Expression Signature to Improve Prognosis Prediction of Stage II and III Colorectal Cancer. J Clin Oncol.
  66. Catalanotto, C., Azzalin, G., Macino, G., and Cogoni, C. (2000). Gene silencing in worms and fungi. Nature 404, 245.
  67. Perdiguero, E., Ruiz-Bonilla, V., Gresh, L., Hui, L., Ballestar, E., Sousa-Victor, P., Baeza- Raja, B., Jardi, M., Bosch-Comas, A., Esteller, M., et al. (2007). Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. EMBO J 26, 1245-1256.
  68. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood 101, 2797-2803.
  69. Gu, S., and Kay, M. A. (2010). How do miRNAs mediate translational repression? Silence 1, 11.
  70. He, T. C., Sparks, A. B., Rago, C., Hermeking, H., Zawel, L., da Costa, L. T., Morin, P. J., Vogelstein, B., and Kinzler, K. W. (1998). Identification of c-MYC as a target of the APC pathway. Science 281, 1509-1512.
  71. Izant, J. G., and Weintraub, H. (1984). Inhibition of thymidine kinase gene expression by anti-sense RNA: a molecular approach to genetic analysis. Cell 36, 1007-1015.
  72. Thompson, C. B., Challoner, P. B., Neiman, P. E., and Groudine, M. (1985). Levels of c- myc oncogene mRNA are invariant throughout the cell cycle. Nature 314, 363-366.
  73. Nau, M. M., Brooks, B. J., Battey, J., Sausville, E., Gazdar, A. F., Kirsch, I. R., McBride, O. W., Bertness, V., Hollis, G. F., and Minna, J. D. (1985). L-myc, a new myc-related gene amplified and expressed in human small cell lung cancer. Nature 318, 69-73.
  74. Ni, H., Wang, X. S., Diener, K., and Yao, Z. (1998). MAPKAPK5, a novel mitogen- activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extracellular-regulated kinase (ERK) and p38 kinase. Biochem Biophys Res Commun 243, 492-496.
  75. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell 17, 37-48.
  76. Gaestel, M. (2006). MAPKAP kinases -MKs -two's company, three's a crowd. Nat Rev Mol Cell Biol 7, 120-130.
  77. Gonzalez, S., Pisano, D. G., and Serrano, M. (2008). Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs. Cell Cycle 7, 2601-2608.
  78. Sampson, V. B., Rong, N. H., Han, J., Yang, Q., Aris, V., Soteropoulos, P., Petrelli, N. J., Dunn, S. P., and Krueger, L. J. (2007). MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67, 9762-9770.
  79. Gallant, P., Shiio, Y., Cheng, P. F., Parkhurst, S. M., and Eisenman, R. N. (1996). Myc and Max homologs in Drosophila. Science 274, 1523-1527.
  80. Guccione, E., Martinato, F., Finocchiaro, G., Luzi, L., Tizzoni, L., Dall' Olio, V., Zardo, G., Nervi, C., Bernard, L., and Amati, B. (2006). Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol 8, 764-770.
  81. Marcu, K. B., Bossone, S. A., and Patel, A. J. (1992). myc function and regulation. Annu Rev Biochem 61, 809-860.
  82. Shachaf, C. M., Kopelman, A. M., Arvanitis, C., Karlsson, A., Beer, S., Mandl, S., Bachmann, M. H., Borowsky, A. D., Ruebner, B., Cardiff, R. D., et al. (2004). MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112-1117.
  83. Nilsson, J. A., and Cleveland, J. L. (2003). Myc pathways provoking cell suicide and cancer. Oncogene 22, 9007-9021.
  84. Seoane, J., Le, H. V., and Massague, J. (2002). Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature 419, 729- 734.
  85. Shen-Ong, G. L., Keath, E. J., Piccoli, S. P., and Cole, M. D. (1982). Novel myc oncogene RNA from abortive immunoglobulin-gene recombination in mouse plasmacytomas. Cell 31, 443-452.
  86. Hui, L., Bakiri, L., Stepniak, E., and Wagner, E. F. (2007b). p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle 6, 2429-2433.
  87. Hui, L., Bakiri, L., Mairhorfer, A., Schweifer, N., Haslinger, C., Kenner, L., Komnenovic, V., Scheuch, H., Beug, H., and Wagner, E. F. (2007a). p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet 39, 741-749.
  88. Guo, S., and Kemphues, K. J. (1995). par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81, 611-620.
  89. Kostenko, S., Johannessen, M., and Moens, U. (2009). PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cell Signal 21, 712-718.
  90. Sun, P., Yoshizuka, N., New, L., Moser, B. A., Li, Y., Liao, R., Xie, C., Chen, J., Deng, Q., Yamout, M., et al. (2007). PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295-308.
  91. Shibata, H., Toyama, K., Shioya, H., Ito, M., Hirota, M., Hasegawa, S., Matsumoto, H., Takano, H., Akiyama, T., Toyoshima, K., et al. (1997). Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science 278, 120-123.
  92. Sears, R., Leone, G., DeGregori, J., and Nevins, J. R. (1999). Ras enhances Myc protein stability. Mol Cell 3, 169-179.
  93. Marinkovic, D., Marinkovic, T., Mahr, B., Hess, J., and Wirth, T. (2004). Reversible lymphomagenesis in conditionally c-MYC expressing mice. Int J Cancer 110, 336-342.
  94. Felsher, D. W., and Bishop, J. M. (1999). Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4, 199-207.
  95. Tabara, H., Grishok, A., and Mello, C. C. (1998). RNAi in C. elegans: soaking in the genome sequence. Science 282, 430-431.
  96. Weigelt, J., Climent, I., Dahlman-Wright, K., and Wikstrom, M. (2001). Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4). Biochemistry 40, 5861-5869.
  97. Wianny, F., and Zernicka-Goetz, M. (2000). Specific interference with gene function by double-stranded RNA in early mouse development. Nat Cell Biol 2, 70-75.
  98. Gaestel, M. (2008). Specificity of signaling from MAPKs to MAPKAPKs: kinases' tango nuevo. Front Biosci 13, 6050-6059.
  99. Otto, T., Horn, S., Brockmann, M., Eilers, U., Schuttrumpf, L., Popov, N., Kenney, A. M., Schulte, J. H., Beijersbergen, R., Christiansen, H., et al. (2009). Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67-78.
  100. van der Horst, A., and Burgering, B. M. (2007). Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8, 440-450.
  101. Jain, M., Arvanitis, C., Chu, K., Dewey, W., Leonhardt, E., Trinh, M., Sundberg, C. D., Bishop, J. M., and Felsher, D. W. (2002). Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102-104.
  102. Reinhart, B. J., Slack, F. J., Basson, M., Pasquinelli, A. E., Bettinger, J. C., Rougvie, A. E., Horvitz, H. R., and Ruvkun, G. (2000). The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901-906.
  103. van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A. P., et al. (2002). The beta- catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111, 241-250.
  104. Wierstra, I., and Alves, J. (2008). The c-myc promoter: still MysterY and challenge. Adv Cancer Res 99, 113-333.
  105. Takai, D., and Jones, P. A. (2003). The CpG island searcher: a new WWW resource. In Silico Biol 3, 235-240.
  106. von der Lehr, N., Johansson, S., Wu, S., Bahram, F., Castell, A., Cetinkaya, C., Hydbring, P., Weidung, I., Nakayama, K., Nakayama, K. I., et al. (2003). The F-box protein Skp2 participates in c-Myc proteosomal degradation and acts as a cofactor for c-Myc-regulated transcription. Mol Cell 11, 1189-1200.
  107. Hermeking, H. (2010). The miR-34 family in cancer and apoptosis. Cell Death Differ 17, 193-199.
  108. Oster, S. K., Ho, C. S., Soucie, E. L., and Penn, L. Z. (2002). The myc oncogene: MarvelouslY Complex. Adv Cancer Res 84, 81-154.
  109. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Radmark, O., Kim, S., and Kim, V. N. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415-419.
  110. Popov, N., Wanzel, M., Madiredjo, M., Zhang, D., Beijersbergen, R., Bernards, R., Moll, R., Elledge, S. J., and Eilers, M. (2007). The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol 9, 765-774.
  111. Wanzel, M., Herold, S., and Eilers, M. (2003). Transcriptional repression by Myc. Trends Cell Biol 13, 146-150.
  112. Vogt, P. K., Jiang, H., and Aoki, M. (2005). Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle 4, 908-913.
  113. Popov, N., Schulein, C., Jaenicke, L. A., and Eilers, M. (2010). Ubiquitylation of the amino terminus of Myc by SCFbeta-TrCP antagonizes SCFFbw7-mediated turnover. Nat Cell Biol 12, 973-981.
  114. Kennerdell, J. R., and Carthew, R. W. (1998). Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell 95, 1017-1026.
  115. Macrae, I. J., Zhou, K., Li, F., Repic, A., Brooks, A. N., Cande, W. Z., Adams, P. D., and Doudna, J. A. (2006). Structural basis for double-stranded RNA processing by Dicer. Science 311, 195-198.
  116. Vervoorts, J., Luscher-Firzlaff, J., and Luscher, B. (2006). The ins and outs of MYC regulation by posttranslational mechanisms. J Biol Chem 281, 34725-34729.
  117. He, L., and Hannon, G. J. (2004). MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5, 522-531.
  118. Cannell, I. G., Kong, Y. W., Johnston, S. J., Chen, M. L., Collins, H. M., Dobbyn, H. C., Elia, A., Kress, T. R., Dickens, M., Clemens, M. J., et al. (2010). p38 MAPK/MK2- mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication. Proc Natl Acad Sci U S A 107, 5375-5380.
  119. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806-811.
  120. Lee, R. C., Feinbaum, R. L., and Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843-854.
  121. Pelengaris, S., Khan, M., and Evan, G. I. (2002). Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321-334.
  122. Pelengaris, S., Littlewood, T., Khan, M., Elia, G., and Evan, G. (1999). Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell 3, 565-577.
  123. Gerits, N., Van Belle, W., and Moens, U. (2007). Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity. Behav Brain Funct 3, 58.
  124. van den Heuvel, A. P., Schulze, A., and Burgering, B. M. (2005). Direct control of caveolin-1 expression by FOXO transcription factors. Biochem J 385, 795-802.
  125. Peukert, K., Staller, P., Schneider, A., Carmichael, G., Hanel, F., and Eilers, M. (1997). An alternative pathway for gene regulation by Myc. EMBO J 16, 5672-5686.
  126. New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L. J., Kato, Y., Parry, G. C., and Han, J. (1998). PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 17, 3372-3384.
  127. Perini, G., Diolaiti, D., Porro, A., and Della Valle, G. (2005). In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proc Natl Acad Sci U S A 102, 12117-12122.
  128. Herbst, A., Hemann, M. T., Tworkowski, K. A., Salghetti, S. E., Lowe, S. W., and Tansey, W. P. (2005). A conserved element in Myc that negatively regulates its proapoptotic activity. EMBO Rep 6, 177-183.
  129. Kops, G. J., Medema, R. H., Glassford, J., Essers, M. A., Dijkers, P. F., Coffer, P. J., Lam, E. W., and Burgering, B. M. (2002). Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors. Mol Cell Biol 22, 2025-2036.
  130. Schmidt, M., Fernandez de Mattos, S., van der Horst, A., Klompmaker, R., Kops, G. J., Lam, E. W., Burgering, B. M., and Medema, R. H. (2002). Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 22, 7842-7852.
  131. Wassenegger, M., Heimes, S., Riedel, L., and Sanger, H. L. (1994). RNA-directed de novo methylation of genomic sequences in plants. Cell 76, 567-576.
  132. Zeller, K. I., Zhao, X., Lee, C. W., Chiu, K. P., Yao, F., Yustein, J. T., Ooi, H. S., Orlov, Y. L., Shahab, A., Yong, H. C., et al. (2006). Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci U S A 103, 17834-17839.
  133. Paik, J. H., Kollipara, R., Chu, G., Ji, H., Xiao, Y., Ding, Z., Miao, L., Tothova, Z., Horner, J. W., Carrasco, D. R., et al. (2007). FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309-323.
  134. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 26, 745-752.
  135. New, L., Jiang, Y., and Han, J. (2003). Regulation of PRAK subcellular location by p38 MAP kinases. Mol Biol Cell 14, 2603-2616.
  136. Shiryaev, A., and Moens, U. (2010). Mitogen-activated protein kinase p38 and MK2, MK3 and MK5: menage a trois or menage a quatre? Cell Signal 22, 1185-1192.
  137. Raingeaud, J., Whitmarsh, A. J., Barrett, T., Derijard, B., and Davis, R. J. (1996). MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 16, 1247-1255.
  138. te Poele, R. H., and Joel, S. P. (1999). Schedule-dependent cytotoxicity of SN-38 in p53 wild-type and mutant colon adenocarcinoma cell lines. Br J Cancer 81, 1285-1293.
  139. C., Chang, C. J., Huang, W. C., et al. (2008). ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol 10, 138-148.
  140. Kong, Y. W., Cannell, I. G., de Moor, C. H., Hill, K., Garside, P. G., Hamilton, T. L., Meijer, H. A., Dobbyn, H. C., Stoneley, M., Spriggs, K. A., et al. (2008). The mechanism of micro-RNA-mediated translation repression is determined by the promoter of the target gene. Proc Natl Acad Sci U S A 105, 8866-8871.
  141. Wei, J. S., Song, Y. K., Durinck, S., Chen, Q. R., Cheuk, A. T., Tsang, P., Zhang, Q., Thiele, C. J., Slack, A., Shohet, J., and Khan, J. (2008). The MYCN oncogene is a direct target of miR-34a. Oncogene 27, 5204-5213.
  142. Cole, M. D., and Cowling, V. H. (2009). Specific regulation of mRNA cap methylation by the c-Myc and E2F1 transcription factors. Oncogene 28, 1169-1175.
  143. Murphy, D. J., Junttila, M. R., Pouyet, L., Karnezis, A., Shchors, K., Bui, D. A., Brown- Swigart, L., Johnson, L., and Evan, G. I. (2008). Distinct thresholds govern Myc's biological output in vivo. Cancer Cell 14, 447-457.
  144. Hannenhalli, S., and Kaestner, K. H. (2009). The evolution of Fox genes and their role in development and disease. Nat Rev Genet 10, 233-240.
  145. Liu, L., Rao, J. N., Zou, T., Xiao, L., Wang, P. Y., Turner, D. J., Gorospe, M., and Wang, J. Y. (2009). Polyamines regulate c-Myc translation through Chk2-dependent HuR phosphorylation. Mol Biol Cell 20, 4885-4898.
  146. M. (1988). Chromosomal translocation in T-cell leukemia line HUT 78 results in a MYC fusion transcript. Proc Natl Acad Sci U S A 85, 9158-9162.
  147. S., Orian, A., Wanzel, M., and Eilers, M. (2010). The Arf tumor suppressor protein inhibits Miz1 to suppress cell adhesion and induce apoptosis. J Cell Biol 188, 905-918.
  148. Choi, S. H., Wright, J. B., Gerber, S. A., and Cole, M. D. (2010). Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells. Genes Dev 24, 1236-1241.
  149. Transcriptional silencing and promoter methylation triggered by double-stranded RNA.
  150. Gan, B., Lim, C., Chu, G., Hua, S., Ding, Z., Collins, M., Hu, J., Jiang, S., Fletcher- Sananikone, E., Zhuang, L., et al. (2010). FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis. Cancer Cell 18, 472-484.
  151. Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G., and Evan, G. I. (1995). A modified oestrogen receptor ligand-binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res 23, 1686-1690.
  152. Miao, H., and Wang, B. (2009). Eph/ephrin signaling in epithelial development and homeostasis. Int J Biochem Cell Biol 41, 762-770.
  153. Sears, R., Nuckolls, F., Haura, E., Taya, Y., Tamai, K., and Nevins, J. R. (2000). Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14, 2501-2514.
  154. Morgenstern, J. P., and Land, H. (1990). Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res 18, 3587-3596.
  155. Sheiness, D., Fanshier, L., and Bishop, J. M. (1978). Identification of nucleotide sequences which may encode the oncogenic capacity of avian retrovirus MC29. J Virol 28, 600-610.
  156. Lutterbach, B., and Hann, S. R. (1994). Hierarchical phosphorylation at N-terminal transformation-sensitive sites in c-Myc protein is regulated by mitogens and in mitosis. Mol Cell Biol 14, 5510-5522.
  157. Shaulian, E., Zauberman, A., Ginsberg, D., and Oren, M. (1992). Identification of a minimal transforming domain of p53: negative dominance through abrogation of sequence-specific DNA binding. Mol Cell Biol 12, 5581-5592.
  158. Sonenberg, N., and Hinnebusch, A. G. (2009). Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731-745.
  159. Siebenlist, U., Bressler, P., and Kelly, K. (1988). Two distinct mechanisms of transcriptional control operate on c-myc during differentiation of HL60 cells. Mol Cell Biol 8, 867-874.
  160. Stone, J., de Lange, T., Ramsay, G., Jakobovits, E., Bishop, J. M., Varmus, H., and Lee, W. (1987). Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol Cell Biol 7, 1697-1709.
  161. Jones, T. R., and Cole, M. D. (1987). Rapid cytoplasmic turnover of c-myc mRNA: requirement of the 3' untranslated sequences. Mol Cell Biol 7, 4513-4521.
  162. Hann, S. R., and Eisenman, R. N. (1984). Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol Cell Biol 4, 2486-2497.
  163. Ramsay, G., Evan, G. I., and Bishop, J. M. (1984). The protein encoded by the human proto-oncogene c-myc. Proc Natl Acad Sci U S A 81, 7742-7746.
  164. Watson, D. K., Psallidopoulos, M. C., Samuel, K. P., Dalla-Favera, R., and Papas, T. S. (1983). Nucleotide sequence analysis of human c-myc locus, chicken homologue, and myelocytomatosis virus MC29 transforming gene reveals a highly conserved gene product.
  165. Li, L. H., Nerlov, C., Prendergast, G., MacGregor, D., and Ziff, E. B. (1994). c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II. EMBO J 13, 4070-4079.
  166. Yada, M., Hatakeyama, S., Kamura, T., Nishiyama, M., Tsunematsu, R., Imaki, H., Ishida, N., Okumura, F., Nakayama, K., and Nakayama, K. I. (2004). Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. EMBO J 23, 2116-2125.
  167. Welcker, M., Orian, A., Jin, J., Grim, J. E., Harper, J. W., Eisenman, R. N., and Clurman, B. E. (2004b). The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A 101, 9085-9090.
  168. Soucek, L., Whitfield, J., Martins, C. P., Finch, A. J., Murphy, D. J., Sodir, N. M., Karnezis, A. N., Swigart, L. B., Nasi, S., and Evan, G. I. (2008). Modelling Myc inhibition as a cancer therapy. Nature 455, 679-683.
  169. Schoenenberger, C. A., Andres, A. C., Groner, B., van der Valk, M., LeMeur, M., and Gerlinger, P. (1988). Targeted c-myc gene expression in mammary glands of transgenic mice induces mammary tumours with constitutive milk protein gene transcription. EMBO J 7, 169-175.
  170. Penn, L. J., Brooks, M. W., Laufer, E. M., and Land, H. (1990). Negative autoregulation of c-myc transcription. EMBO J 9, 1113-1121.
  171. McMahon, S. B., Wood, M. A., and Cole, M. D. (2000). The essential cofactor TRRAP recruits the histone acetyltransferase hGCN5 to c-Myc. Mol Cell Biol 20, 556-562.
  172. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol 20, 8969-8982.
  173. Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21, 952-965.
  174. Herold, S., Wanzel, M., Beuger, V., Frohme, C., Beul, D., Hillukkala, T., Syvaoja, J., Saluz, H. P., Haenel, F., and Eilers, M. (2002). Negative regulation of the mammalian UV response by Myc through association with Miz-1. Mol Cell 10, 509-521.
  175. Shi, Y., Kotlyarov, A., Laabeta, K., Gruber, A. D., Butt, E., Marcus, K., Meyer, H. E., Friedrich, A., Volk, H. D., and Gaestel, M. (2003). Elimination of protein kinase MK5/PRAK activity by targeted homologous recombination. Mol Cell Biol 23, 7732- 7741.
  176. Christoffersen, N. R., Shalgi, R., Frankel, L. B., Leucci, E., Lees, M., Klausen, M., Pilpel, Y., Nielsen, F. C., Oren, M., and Lund, A. H. (2010). p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 17, 236- 245.

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