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The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila

Nature Cell Biology volume 5, pages 921–927 (2003)Cite this article

Abstract

Tissue growth during animal development is tightly controlled so that the organism can develop harmoniously1. The salvador (sav) gene, which encodes a scaffold protein, has been shown to restrict cell number by coordinating cell-cycle exit and apoptosis during Drosophila development2,3. Here we identify Hippo (Hpo), the Drosophila orthologue of the mammalian MST1 and MST2 serine/threonine kinases, as a partner of Sav. Loss of hpo function leads to sav-like phenotypes, whereas gain of hpo function results in the opposite phenotype. Whereas Sav and Hpo normally restrict cellular quantities of the Drosophila inhibitor of apoptosis protein DIAP1, overexpression of Hpo destabilizes DIAP1 in cell culture. We show that DIAP1 is phosphorylated in a Hpo-dependent manner in S2 cells and that Hpo can phosphorylate DIAP1 in vitro. Thus, Hpo may promote apoptosis by reducing cellular amounts of DIAP1. In addition, we show that Sav is an unstable protein that is stabilized by Hpo. We propose that Hpo and Sav function together to restrict tissue growth in vivo.

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Figure 1: Salvador and Wts interact with Hpo.
Figure 2: RNAi-mediated hpo LOF induces organ overgrowth.
Figure 3: hpo downregulation prevents cell-cycle exit and apoptosis in the eye imaginal disc.
Figure 4: Hpo induces DIAP1 and Sav phosphorylation, and modulates their stability.

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References

  1. Conlon, I. & Raff, M. Size control in animal development. Cell 96, 235–244 (1999).

    Article  CAS  Google Scholar 

  2. Tapon, N. et al. salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467–478 (2002).

    Article  CAS  Google Scholar 

  3. Kango-Singh, M. et al. Shar-pei mediates cell proliferation arrest during imaginal disc growth in Drosophila. Development 129, 5719–5730 (2002).

    Article  CAS  Google Scholar 

  4. Edgar, B.A. & Lehner, C.F. Developmental control of cell cycle regulators: a fly's perspective. Science 274, 1646–1652 (1996).

    Article  CAS  Google Scholar 

  5. Bergmann, A., Agapite, J. & Steller, H. Mechanisms and control of programmed cell death in invertebrates. Oncogene 17, 3215–3223 (1998).

    Article  Google Scholar 

  6. Ditzel, M. & Meier, P. IAP degradation: decisive blow or altruistic sacrifice? Trends Cell Biol. 12, 449–452 (2002).

    Article  CAS  Google Scholar 

  7. Justice, R.W., Zilian, O., Woods, D.F., Noll, M. & Bryant, P.J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534–546 (1995).

    Article  CAS  Google Scholar 

  8. Xu, T., Wang, W., Zhang, S., Stewart, R.A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Drosophila lats gene encodes a putative protein kinase. Development 121, 1053–1063 (1995).

    CAS  PubMed  Google Scholar 

  9. Dan, I., Watanabe, N.M. & Kusumi, A. The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol. 11, 220–230 (2001).

    Article  CAS  Google Scholar 

  10. Cheung, W.L. et al. Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113, 507–517 (2003).

    Article  CAS  Google Scholar 

  11. Wang, H.C. & Fecteau, K.A. Detection of a novel quiescence-dependent protein kinase. J. Biol. Chem. 275, 25850–25857 (2000).

    Article  CAS  Google Scholar 

  12. Giordano, E., Rendina, R., Peluso, I. & Furia, M. RNAi triggered by symmetrically transcribed transgenes in Drosophila melanogaster. Genetics 160, 637–648 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Pignoni, F. & Zipursky, S.L. Induction of Drosophila eye development by decapentaplegic. Development 124, 271–278 (1997).

    CAS  PubMed  Google Scholar 

  14. Grether, M.E., Abrams, J.M., Agapite, J., White, K. & Steller, H. The head involution defective gene of Drosophila melanogaster functions in programmed cell death. Genes Dev. 9, 1694–1708 (1995).

    Article  CAS  Google Scholar 

  15. Ring, J.M. & Martinez Arias, A. puckered, a gene involved in position-specific cell differentiation in the dorsal epidermis of the Drosophila larva. Development (suppl.), 251–259 (1993).

  16. Weston, C.R. & Davis, R.J. The JNK signal transduction pathway. Curr. Opin. Genet. Dev. 12, 14–21 (2002).

    Article  CAS  Google Scholar 

  17. Moreno, E., Yan, M. & Basler, K. Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily. Curr. Biol. 12, 1263–1268 (2002).

    Article  CAS  Google Scholar 

  18. Igaki, T. et al. Eiger, a TNF superfamily ligand that triggers the Drosophila JNK pathway. EMBO J. 21, 3009–3018 (2002).

    Article  CAS  Google Scholar 

  19. Sluss, H.K., Han, Z., Barrett, T., Davis, R.J. & Ip, Y.T. A JNK signal transduction pathway that mediates morphogenesis and an immune response in Drosophila. Genes Dev. 10, 2745–2758 (1996).

    Article  CAS  Google Scholar 

  20. Riesgo-Escovar, J.R., Jenni, M., Fritz, A. & Hafen, E. The Drosophila Jun-N-terminal kinase is required for cell morphogenesis but not for DJun-dependent cell fate specification in the eye. Genes Dev. 10, 2759–2768 (1996).

    Article  CAS  Google Scholar 

  21. Wang, S.L., Hawkins, C.J., Yoo, S.J., Muller, H.A. & Hay, B.A. The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Cell 98, 453–463 (1999).

    Article  CAS  Google Scholar 

  22. Goyal, L., McCall, K., Agapite, J., Hartwieg, E. & Steller, H. Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. EMBO J. 19, 589–597 (2000).

    Article  CAS  Google Scholar 

  23. Wilson, R. et al. The DIAP1 RING finger mediates ubiquitination of Dronc and is indispensable for regulating apoptosis. Nature Cell Biol. 4, 445–450 (2002).

    Article  CAS  Google Scholar 

  24. Yoo, S.J. et al. Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms. Nature Cell Biol. 4, 416–424 (2002).

    Article  CAS  Google Scholar 

  25. Wing, J.P. et al. Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Nature Cell Biol. 4, 451–456 (2002).

    Article  CAS  Google Scholar 

  26. Ryoo, H.D., Bergmann, A., Gonen, H., Ciechanover, A. & Steller, H. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Nature Cell Biol. 4, 432–438 (2002).

    Article  CAS  Google Scholar 

  27. Holley, C.L., Olson, M.R., Colon-Ramos, D.A. & Kornbluth, S. Reaper eliminates IAP proteins through stimulated IAP degradation and generalized translational inhibition. Nature Cell Biol. 4, 439–444 (2002).

    Article  CAS  Google Scholar 

  28. Hays, R., Wickline, L. & Cagan, R. Morgue mediates apoptosis in the Drosophila melanogaster retina by promoting degradation of DIAP1. Nature Cell Biol. 4, 425–431 (2002).

    Article  CAS  Google Scholar 

  29. Ditzel, M. et al. Degradation of DIAP1 by the N-end rule pathway is essential for regulating apoptosis. Nature Cell Biol. 5, 467–473 (2003).

    Article  CAS  Google Scholar 

  30. Finley, R.L. Jr, Thomas, B.J., Zipursky, S.L. & Brent, R. Isolation of Drosophila cyclin D, a protein expressed in the morphogenetic furrow before entry into S phase. Proc. Natl Acad. Sci. USA 93, 3011–3015 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank I. Hariharan, S. Noselli, S. Schelble, H. Steller and K. White for fly stocks; R. Finley, C Ghiglione, E. Giordano, R. Hays, A.-O. Hueber, A. Plessis, J. Pouysségur's laboratory, L. Ruel and K. White for plasmids and reagents; R. Arkowitz and his laboratory for help with the yeast two-hybrid assay; R. Arkowitz, B. Hay, and H. Richardson for antibodies; I. Hariharan, K. Harvey, C. Pfleger and G. Halder for discussing data before publication; M.-T. Ravier for technical assistance; and members of the Léopold, Thérond and Noselli laboratories for discussions. This work was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Association pour la Recherche contre le Cancer, the Ligue Nationale Contre le Cancer, and the Association pour la Sclérose Tubéreuse de Bourneville.

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  1. Nicolas Tapon

    Present address: Apoptosis and Proliferation Control Laboratory, Cancer Research UK London Research Institute, PO Box 123, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

  2. Sophie Pantalacci and Nicolas Tapon: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Signalling, Developmental Biology and Cancer Research, CNRS UMR 6543, Centre de Biochimie, Université de Nice, Nice, 06108, Cedex 2, France

    Sophie Pantalacci, Nicolas Tapon & Pierre Léopold

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  1. Sophie Pantalacci
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Correspondence to Nicolas Tapon.

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Pantalacci, S., Tapon, N. & Léopold, P. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol 5, 921–927 (2003). https://doi.org/10.1038/ncb1051

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