Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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The Fungal Metabolite Brefeldin A Inhibits Dvl2-Plk1-Dependent Primary Cilium Disassembly

  • Lee, Uijeong (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim, Sun-Ok (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Hwang, Jeong-Ah (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Jang, Jae-Hyuk (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Son, Sangkeun (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Ryoo, In-Ja (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Ahn, Jong Seog (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim, Bo Yeon (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Lee, Kyung Ho (World Class Institute (WCI), Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
  • Received : 2017.03.03
  • Accepted : 2017.05.11
  • Published : 2017.06.30
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Abstract

The primary cilium is a non-motile microtubule-based organelle that protrudes from the surface of most human cells and works as a cellular antenna to accept extracellular signals. Primary cilia assemble from the basal body during the resting stage ($G_0$ phase) and simultaneously disassemble with cell cycle re-entry. Defective control of assembly or disassembly causes diverse human diseases including ciliopathy and cancer. To identify the effective compounds for studying primary cilium disassembly, we have screened 297 natural compounds and identified 18 and 17 primary cilium assembly and disassembly inhibitors, respectively. Among them, the application of KY-0120, identified as Brefeldin A, disturbed Dvl2-Plk1-mediated cilium disassembly via repression of the interaction of $CK1{\varepsilon}-Dvl2$ and the expression of Plk1 mRNA. Therefore, our study may suggest useful compounds for studying the cellular mechanism of primary cilium disassembly to prevent ciliopathy and cancer.

Keywords

References

  1. Barr, F.A., Sillje, H.H., and Nigg, E.A. (2004). Polo-like kinases and the orchestration of cell division. Nat. Rev. Mol. Cell Biol. 5, 429-440.
  2. Bryja, V., Schulte, G., Rawal, N., Grahn, A., and Arenas, E. (2007). Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism. J. Cell Sci. 120, 586-595. https://doi.org/10.1242/jcs.03368
  3. Charles, J.F., Jaspersen, S.L., Tinker-Kulberg, R.L., Hwang, L., Szidon, A., and Morgan, D.O. (1998). The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae. Curr. Biol. 8, 497-507. https://doi.org/10.1016/S0960-9822(98)70201-5
  4. Colanzi, A., Grimaldi, G., Catara, G., Valente, C., Cericola, C., Liberali, P., Ronci, M., Lalioti, V.S., Bruno, A., Beccari, A.R., et al. (2013). Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS. Proc. Natl. Acad. Sci. USA 110, 9794-9799. https://doi.org/10.1073/pnas.1222413110
  5. Goetz, S.C., and Anderson, K.V. (2010). The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331-344. https://doi.org/10.1038/nrg2774
  6. Gonzalez-Sancho, J.M., Greer, Y.E., Abrahams, C.L., Takigawa, Y., Baljinnyam, B., Lee, K.H., Lee, K.S., Rubin, J.S., and Brown, A.M. (2013). Functional consequences of Wnt-induced dishevelled 2 phosphorylation in canonical and noncanonical Wnt signaling. J. Biol. Chem. 288, 9428-9437. https://doi.org/10.1074/jbc.M112.448480
  7. Gradilone, S.A., Radtke, B.N., Bogert, P.S., Huang, B.Q., Gajdos, G.B., and LaRusso, N.F. (2013). HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res. 73, 2259-2270. https://doi.org/10.1158/0008-5472.CAN-12-2938
  8. Han, Y.G., Kim, H.J., Dlugosz, A.A. Ellison, D.W., Gilbertson, R.J., and Alvarez-Buylla, A. (2009). Dual and opposing roles of primary cilia in medulloblastoma development. Nat. Med. 15, 1062-1065. https://doi.org/10.1038/nm.2020
  9. Hoffmeister, H., Babinger, K., Gürster, S., Cedzich, A., Meese, C., Schadendorf, K., Osten, L., de Vries, U., Rascle, A., and Witzgall, R. (2011). Polycystin-2 takes different routes to the somatic and ciliary plasma membrane. J. Cell Biol. 192, 631-645. https://doi.org/10.1083/jcb.201007050
  10. Kim, J., Dabiri, S., and Seeley, E.S. (2011). Primary cilium depletion typifies cutaneous melanoma in situ and malignant melanoma. PLoS One 6, e27410. https://doi.org/10.1371/journal.pone.0027410
  11. Kingsbury, J.M., and Cardenas, M.E. (2016). Vesicular trafficking systems impact TORC1-controlled transcriptional programs in Saccharomyces cerevisiae. G3 (Bethesda). 6, 641-652.
  12. Kishida, M., Hino, S.I., Michiue, T., Yamamoto, H., Kishida, S., Fukui, A., Asashima, M., and Kikuchi, A. (2001). A. Fukui, M. Asashima, A. Kikuchi, Synergistic activation of the Wnt signaling pathway by Dvl and casein kinase $I{\varepsilon}$. J. Biol Chem. 276, 33147-33155. https://doi.org/10.1074/jbc.M103555200
  13. Klausner, R.D., Donaldson, J.G., and Lippincott-Schwartz, J. (1992). Brefeldin A: insights into the control of membrane traffic and organelle structure. J. Cell Biol. 116, 1071-1080. https://doi.org/10.1083/jcb.116.5.1071
  14. Knecht, R., Elez, R., Oechler, M., Solbach, C., von Ilberg, C., and Strebhardt, K. (1999). Prognostic significance of polo-like kinase (PLK) expression in squamous cell carcinomas of the head and neck. Cancer Res. 59, 2794-2797.
  15. Lee, K.H., Johmura, Y., Yu, L.R., Park, J.E., Gao, Y., Bang, J.K., Zhou, M., Veenstra, T.D., Kim, B.Y., and Lee, K.S. (2012). Identification of a novel Wnt5a-$CK1{\varepsilon}$-Dvl2-Plk1- mediated primary cilia disassembly pathway. EMBO J. 31, 3104-3117. https://doi.org/10.1038/emboj.2012.144
  16. MacDonald, B.T., Tamai, K., and He, X. (2009). Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell 17, 9-26. https://doi.org/10.1016/j.devcel.2009.06.016
  17. Mockel, A., Perdomo, Y., Stutzmann, F., Letsch, J., Marion, V., and Dollfus, H. (2011). Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog. Retin. Eye Res. 30, 258-274. https://doi.org/10.1016/j.preteyeres.2011.03.001
  18. Moser, J.J., Fritzler, M.J., and Rattner, J.B. (2009). Primary ciliogenesis defects are associated with human astrocytoma/glioblastoma cells. BMC Cancer 488, 1-12.
  19. Nachury, M.V., Loktev, A.V., Zhang, Q., Westlake, C.J., Peranen, J., Merdes, A., Slusarski, D.C., Scheller, R.H., Bazan, J.F., Sheffield, V.C., et al. (2007). A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129, 1201-1213. https://doi.org/10.1016/j.cell.2007.03.053
  20. Nylander, S., and Kalies, I. (1999). Brefeldin A, but not monensin, completely blocks CD69 expression on mouse lymphocytes: efficacy of inhibitors of protein secretion in protocols for intracellular cytokine staining by flow cytometry. J. Immunol. Methods 224, 69-76. https://doi.org/10.1016/S0022-1759(99)00010-1
  21. Pahl. H.L., and Baeuerle, P.A. (1995). A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B. EMBO J. 14, 2580-2588.
  22. Park, T.J., Haigo, S.L., and Wallingford, J.B. (2006). Ciliogenesis defects in embryos lacking inturned or fuzzy function are associated with failure of planar cell polarity and Hedgehog signaling. Nat. Genet. 38, 303-311. https://doi.org/10.1038/ng1753
  23. Peluso, M.O., Campbell, V.T., Harari, J.A., Tibbitts, T.T., Proctor, J.L., Whitebread, N., Conley, J.M., White, K.F., Kutok, J.L., Read, M.A., McGovern, K., and Faia, K.L. (2014). Impact of the Smoothened inhibitor, IPI-926, on smoothened ciliary localization and Hedgehog pathway activity. PLoS One 9, e90534. https://doi.org/10.1371/journal.pone.0090534
  24. Peters, J.M., McKay, R.M., McKay, J.P., and Graff, J.M. (1999). Casein kinase I transduces Wnt signals. Nature 401, 345-350. https://doi.org/10.1038/43830
  25. Petronczki, M., Lenart, P., and Peters, J.M. (2008). Polo on the Risefrom Mitotic Entry to Cytokinesis with Plk1. Dev. Cell 14, 646-659. https://doi.org/10.1016/j.devcel.2008.04.014
  26. Pugacheva, E.N., Jablonski, S.A., Hartman, T.R., Henske, E.P., and Golemis, E.A. (2007). HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351-1363. https://doi.org/10.1016/j.cell.2007.04.035
  27. Rena, G., Bain, J., Elliott, M., and Cohen, P. (2004). D4476, a cellpermeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of FOXO1a. EMBO Rep. 5, 60-65. https://doi.org/10.1038/sj.embor.7400048
  28. Rohatgi, R., Milenkovic, L., and Scott, M.P. (2007). Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372-376. https://doi.org/10.1126/science.1139740
  29. Rosa, P., Mantovani, S., Rosboch, R., and Huttner, W.B. (1992). Monensin and brefeldin A differentially affect the phosphorylation and sulfation of secretory proteins. J. Biol. Chem. 267, 12227-12232.
  30. Santos, N., and Reiter, J.F. (2008). Building it up and taking it down: the regulation of vertebrate ciliogenesis. Dev. Dyn. 237, 1972-1981. https://doi.org/10.1002/dvdy.21540
  31. Satir, P., and Christensen, S.T. (2008). Structure and function of mammalian cilia, Histochem. Cell Biol. 129, 687-693.
  32. Seeley, E.S., and Nachury, M.V. (2010). The perennial organelle: assembly and disassembly of the primary cilium. J. Cell Sci. 123, 511-518. https://doi.org/10.1242/jcs.061093
  33. Shirayama, M., Zachariae, W., Ciosk, R., and Nasmyth, K. (1998). The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. EMBO J. 17, 1336-1349. https://doi.org/10.1093/emboj/17.5.1336
  34. Singh, J., Yanfeng, W.A., Grumolato, L., Aaronson, S.A., and Mlodzik, M. (2010). Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation. Genes Dev. 24, 2157-2168. https://doi.org/10.1101/gad.1961010
  35. Strebhardt, K., and Ullrich, A. (2006). Targeting polo-like kinase 1 for cancer therapy. Nat. Rev. Cancer 6, 321-330. https://doi.org/10.1038/nrc1841
  36. Tseng, C.N., Hong, Y.R., Chang, H.W., Yu, T.J., Hung, T.W., Hou, M.F., Yuan, S.S., Cho, C.L., Liu, C.T., Chiu, C.C., et al. (2014). Brefeldin A reduces anchorage-independent survival, cancer stem cell potential and migration of MDA-MB-231 human breast cancer cells. Molecules 19, 17464-17477. https://doi.org/10.3390/molecules191117464
  37. von Schubert, C., Cubizolles, F., Bracher, J.M., Sliedrecht, T., Kops, G.J., and Nigg, E.A. (2015). Plk1 and Mps1 cooperatively regulate the spindle assembly checkpoint in human cells. Cell Rep. 12, 66-78. https://doi.org/10.1016/j.celrep.2015.06.007
  38. Wong, S.Y., Seol, A.D., So, P.L., Ermilov, A.N., Bichakjian, C.K., Epstein, E.H. Jr., Dlugosz, A.A., and Reiter, J.F. (2009). Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat. Med. 9, 1055-1061.
  39. Wyrozumska. P., Ashley. J.W., Ramanadham. S., Liu. Q., Garvey. W.T., and Sztul. E. (2014). Novel effects of Brefeldin A (BFA) in signaling through the insulin receptor (IR) pathway and regulating FoxO1-mediated transcription. Cell Logist. 4, e27732. https://doi.org/10.4161/cl.27732
  40. Xiang, W., Jiang, T., Guo, F., Gong, C., Yang, K., Wu, Y., Huang, X., Cheng, W., and Xu, K. (2014). Hedgehog pathway inhibitor-4 suppresses malignant properties of chondrosarcoma cells by disturbing tumor ciliogenesis. Oncol. Rep. 32, 1622-1630. https://doi.org/10.3892/or.2014.3372

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