Regulation of epithelial integrity and organ growth by Tctp and Coracle in Drosophila

Autoři: Sung-Ryeong Lee aff001;  Sung-Tae Hong aff002;  Kwang-Wook Choi aff001
Působiště autorů: Department of Biological Sciences, Korean Advanced Institute of Science and Technology, Daejeon, Republic of Korea aff001;  Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea aff001;  Department of Anatomy & Cell Biology, Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, Republic of Korea aff002
Vyšlo v časopise: Regulation of epithelial integrity and organ growth by Tctp and Coracle in Drosophila. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008885
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008885


Regulation of cell junctions is crucial for the integrity of epithelial tissues and organs. Cell junctions also play roles in controlling cell proliferation for organ growth. Translationally controlled tumor protein (TCTP) is a conserved protein involved in growth control, but its role in cell junctions is unknown. Here we show that Drosophila Tctp directly interacts with the septate junction protein Coracle (Cora) to regulate epithelial integrity and organ growth. Tctp localizes together with Cora in the epidermis of the embryo. Loss of Cora reduces the level of Tctp in the epidermis but not vice versa. cora/+ or Tctp/+ single heterozygotes develop normally to adulthood. However, double heterozygotes for cora and Tctp mutations show severe disruption of epithelia causing synthetic lethality in the embryo. Double knockdown of Cora and Tctp in eye imaginal disc synergistically leads to disruption of the eye disc, resulting in a severe reduction or loss of eye and head. Conversely, double knockdown of Cora and Tctp in wing disc causes overgrowth as well as cell death. Inhibition of cell death under this condition causes hyperplastic growth of the wing disc. Tctp also shows direct and functional interaction with Cora-associated factors like Yurt and Na+/K+-ATPase. This study suggests that proper levels of Tctp and Cora are essential for the maintenance of the Cora complex and the integrity of epithelia. Our data also provide evidence that both Cora and Tctp are required to suppress overgrowth in developing wing.

Klíčová slova:

Cell membranes – DAPI staining – Drosophila melanogaster – Embryos – Eyes – Genetic interactions – RNA interference – Septate junctions


1. Koziol MJ and Gurdon JB. TCTP in development and cancer. Biochemistry research international. 2012;2012:105203. doi: 10.1155/2012/105203 22649730

2. Telerman A and Amson R. The molecular programme of tumour reversion: the steps beyond malignant transformation. Nature Reviews Cancer 2009;9(3):206–16. doi: 10.1038/nrc2589 19180095

3. Nagano-Ito M and Ichikawa S. Biological Effects of Mammalian Translationally Controlled Tumor Protein (TCTP) on Cell Death, Proliferation, and Tumorigenesis. Biochemistry research international 2012;204960. doi: 10.1155/2012/204960 22675633

4. Thiele H, Berger M, Skalweit A, Thiele BJ. Expression of the gene and processed pseudogenes encoding the human and rabbit translationally controlled turnout protein (TCTP). European Journal of Biochemistry. 2000;267(17):5473–81. doi: 10.1046/j.1432-1327.2000.01609.x 10951206

5. Guillaume E, Pineau C, Evrard B, Dupaix A, Moertz E, Sanchez JC et al. Cellular distribution of translationally controlled tumor protein in rat and human testes. Proteomics. 2001;1(7):880–9. doi: 10.1002/1615-9861(200107)1:7<880::AID-PROT880>3.0.CO;2-2 11503212

6. Tuynder M, Susini L, Prieur S, Besse S, Fiucci G, Amson R et al. Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(23):14976–81. doi: 10.1073/pnas.222470799 12399545

7. Tuynder M, Fiucci G, Prieur S, Lespagnol A, Géant A, Beaucourt S et al. Translationally controlled tumor protein is a target of tumor reversion. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(43):15364–9. doi: 10.1073/pnas.0406776101 15489264

8. Gachet Y, Tournier S, Lee M, Lazaris-Karatzas A, Poulton T, Bommer UA. The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle. Journal of Cell Science. 1999;112:1257–71. 10085260

9. Yarm FR. Plk phosphorylation regulates the microtubule-stabilizing protein TCTP. Molecular and cellular biology. 2002;22(17):6209–21. doi: 10.1128/mcb.22.17.6209-6221.2002 12167714

10. Rho SB, Lee JH, Park MS, Byun HJ, Kang S, Seo SS et al. Anti-apoptotic protein TCTP controls the stability of the tumor suppressor p53. FEBS Letters. 2011;585(1):29–35. doi: 10.1016/j.febslet.2010.11.014 21081126

11. Yang Y, Yang F, Xiong Z, Yan Y, Wang X, Nishino M et al. An N-terminal region of translationally controlled tumor protein is required for its antiapoptotic activity. Oncogene. 2005;24(30):4778–88. doi: 10.1038/sj.onc.1208666 15870695

12. Hsu YC, Chern JJ, Cai Y, Liu M and Choi KW. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature. 2007;445(7129):785–8. doi: 10.1038/nature05528 17301792

13. Inoki K, Li Y, Xu T and Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & development. 2003;17(15):1829–34.

14. Berkowitz O, Jost R, Pollmann S and Masle J. Characterization of TCTP, the translationally controlled tumor protein, from Arabidopsis thaliana. Plant Cell 2008;20(12):3430–47. doi: 10.1105/tpc.108.061010 19060111

15. Kim DK, Nam BY, Li JJ, Park JT, Lee SH, Kim DH et al. Translationally controlled tumour protein is associated with podocyte hypertrophy in a mouse model of type 1 diabetes. Diabetologia 2012;55(4): 1205–17. doi: 10.1007/s00125-012-2467-7 22311416

16. Kobayashi D, Hirayama M, Komohara Y, Mizuguchi S, Wilson Morifuji M, Ihn H et al. Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1-associated tumors. Journal of Biological Chemistry. 2014;289(38):26314–26. doi: 10.1074/jbc.M114.568253 25092287

17. Dong X, Yang B, Li Y, Zhong C and Ding J. Molecular basis of the acceleration of the GDP-GTP exchange of human Rheb by human TCTP. Journal of Biological Chemistry. 2009;284(35):23754–64. doi: 10.1074/jbc.M109.012823 19570981

18. Zhang J, de Toledo SM, Pandey BN, Guo G, Pain D, Li H et al. Role of the translationally controlled tumor protein in DNA damage sensing and repair. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(16):E926–33. doi: 10.1073/pnas.1106300109 22451927

19. Hong ST and Choi KW. TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster. Nature Communications. 2013;4:2986. doi: 10.1038/ncomms3986 24352200

20. Hong ST and Choi KW. Antagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences. Nature Communications. 2016;7:12988. doi: 10.1038/ncomms12988 27687497

21. Karaman R. and Halder G. Cell Junctions in Hippo Signaling. Cold Spring Harb Perspect Biol. 2018;10(5): pii: a028753. doi: 10.1101/cshperspect.a028753 28600393

22. Tepass U, Tanentzapf G, Ward R, Fehon R. Epithelial cell polarity and cell junctions in Drosophila. Annual Reveiws of Genetics. 2001;35:747–84.

23. Bilder D. Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes & Development. 2004;18(16):1909–25.

24. Hariharan IK, Bilder D. Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annual Review of Genetics. 2006;40:335–61. doi: 10.1146/annurev.genet.39.073003.100738 16872256

25. Gateff E, Schneiderman HA. Developmental studies of new mutant of Drosophila melanogaster: lethal malignant brain tumor. American Zoologist. 1967;7:760.

26. Woods DF, Bryant PJ. Molecular cloning of the lethal(1) discs large-1 oncogene of Drosophila. Developmental Biology. 1989;134(1):222–35. doi: 10.1016/0012-1606(89)90092-4 2471660

27. Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature. 2000;403(6770):676–80. doi: 10.1038/35001108 10688207

28. Laprise P, Lau KM, Harris KP, Silva-Gagliardi NF, Paul SM, Beronja S et al. Yurt, Coracle, Neurexin IV and the Na+,K+-ATPase form a novel group of epithelial polarity proteins. Nature. 2009;459(7250):1141–5. doi: 10.1038/nature08067 19553998

29. Fehon RG, Dawson IA, Artravanis-Tsakonas S. A Drosophila homologue of membrane-skeleton protein 4.1 is associated with septate junctions and is encoded by the coracle gene. Development. 1994;120(3):545–57. 8162854

30. Lamb RS, Ward RE, Schweizer L and Fehon RG. Drosophila coracle, a member of the protein 4.1 superfamily, has essential structural functions in the septate junctions and developmental functions in embryonic and adult epithelial cells. Molecular biology of the cell. 1998;9(12):3505–19. doi: 10.1091/mbc.9.12.3505 9843584

31. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993;118(2):401–15. 8223268

32. Ward RE, Lamb RS and Fehon RG. A conserved functional domain of Drosophila coracle is required for localization at the septate junction and has membrane-organizing activity. The Journal of cell biology. 1998;140(6):1463–73. doi: 10.1083/jcb.140.6.1463 9508778

33. Schejter ED, Wieschaus E. Functional elements of the cytoskeleton in the early Drosophila embryo. Annual review of cell biology. 1993;9:67–99. doi: 10.1146/annurev.cb.09.110193.000435 8280474

34. Sokac AM, Wieschaus E. Zygotically controlled F-actin establishes cortical compartments to stabilize furrows during Drosophila cellularization. J Cell Sci. 2008;121(11):1815–24. doi: 10.1242/jcs.025171 18460582

35. Ward RE, Schweizer L, Lamb RS, Fehon RG. The protein 4.1, ezrin, radixin, moesin (FERM) domain of Drosophila Coracle, a cytoplasmic component of the septate junction, provides functions essential for embryonic development and imaginal cell proliferation. Genetics. 2001;159(1):219–28. 11560899

36. Struhl G, Basler K. Organizing activity of wingless protein in Drosophila. Cell. 1993;72(4):527–40. doi: 10.1016/0092-8674(93)90072-x 8440019

37. Laprise P, Beronja S, Silva-Gagliardi NF, Pellikka M, Jensen AM, McGlade CJ et al. The FERM protein Yurt is a negative regulatory component of the Crumbs complex that controls epithelial polarity and apical membrane size. Developmental cell. 2006;11(3):363–74. doi: 10.1016/j.devcel.2006.06.001 16950127

38. Jung J, Kim M, Kim MJ, Kim J, Moon J, Lim JS et al. Translationally controlled tumor protein interacts with the third cytoplasmic domain of Na,K-ATPase alpha subunit and inhibits the pump activity in HeLa cells. Journal of Biological Chemistry. 2004;279(48):49868–75. doi: 10.1074/jbc.M400895200 15383549

39. Gamblin CL, Hardy ÉJ, Chartier FJ, Bisson N and Laprise P. A bidirectional antagonism between aPKC and Yurt regulates epithelial cell polarity. The Journal of cell biology. 2014;204(4):487–95. doi: 10.1083/jcb.201308032 24515345

40. Ryoo HD, Gorenc T, Steller H. Apoptotic Cells Can Induce Compensatory Cell Proliferation through the JNK and the Wingless Signaling Pathways. Developmental Cell. 2004;7(4):491–501. doi: 10.1016/j.devcel.2004.08.019 15469838

41. Jaklevic BR, Su TT. Relative contribution of DNA repair, cell cycle checkpoints, and cell death to survival after DNA damage in Drosophila larvae. Current Biology. 2004;14(1):23–32. doi: 10.1016/j.cub.2003.12.032 14711410

42. Huh JR, Guo M, Hay BA. Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role. Current Biology. 2004;14(14):1262–6. doi: 10.1016/j.cub.2004.06.015 15268856

43. Fan Y, Bergmann A. Apoptosis-induced compensatory proliferation. The Cell is dead. Long live the Cell! Trends in Cell Biology. 2008;18(10):467–73. doi: 10.1016/j.tcb.2008.08.001 18774295

44. Schneider G, Schmidt-Supprian M, Rad R, Saur D. Tissue-specific tumorigenesis: context matters. Nat Rev Cancer. 2017;17(4):239–53. doi: 10.1038/nrc.2017.5 28256574

45. Aster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annual review of pathology. 2017;12:245–75. doi: 10.1146/annurev-pathol-052016-100127 27959635

46. Shen L, Shi Q, Wang W. Double agents: genes with both oncogenic and tumor-suppressor functions. Oncogenesis. 2018;7(3):25. doi: 10.1038/s41389-018-0034-x 29540752

47. Szabad J, Jursnich VA, Bryant PJ. Requirement for cell-proliferation control genes in Drosophila oogenesis. Genetics. 1991;127(3):525–33. 2016052

48. Baines AJ, Lu HC, Bennett PM. The Protein 4.1 family: hub proteins in animals for organizing membrane proteins. Biochimica et Biophysica. Acta (BBA)–Biomembranes. 2014;1838(2):605–19. doi: 10.1016/j.bbamem.2013.05.030 23747363

49. Thurmond J, Goodman JL, Strelets VB, Attrill H, Gramates LS, Marygold SJ. FlyBase 2.0: the next generation. Nucleic Acids Research. 2018;47:759–65. doi: 10.1093/nar/gky1003 30364959

50. Cyrille A, Christian D. Drosophila: Methods and Protocols. Methods in molecular biology. 2008;420:197–205. doi: 10.1007/978-1-59745-583-1_11 18641948

51. Yeom EB, Hong ST, Choi KW. Crumbs interacts with Xpd for nuclear division control in Drosophila. Oncogene. 2015;34:2777–89. doi: 10.1038/onc.2014.202 25065591

52. Tartof KD, Hobbs CA. Improved media for growing plasmid and cosmid clones. BRL Focus 1987;9(2):12.

53. Foe VE, Alberts BM. Studies of nuclear and cytoplasmic behavior during the five mitotic cycles that precede gastrulation in Drosophila embryogenesis. Journal of cell science. 1983;61:31–70. 6411748

54. Mitchison TJ, Sedat J. Localization of antigenic determinants in whole Drosophila embryos. Developmental Biology. 1983;99(1):261–4. doi: 10.1016/0012-1606(83)90275-0 6194030

55. Carroll SB, Whyte JS. The role of the hairy gene during Drosophila morphogenesis: stripes in imaginal discs. Genes & Development. 1989;3:905–16. doi: 10.1101/gad.3.6.905

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