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Gene Review

th  -  thread

Drosophila melanogaster

Synonyms: 0736/01, 1065/03, Apoptosis 1 inhibitor, CG12284, D-IAP1, ...
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Disease relevance of th

  • Sequence analysis of these alleles revealed that they were caused by single amino acid changes in the baculovirus IAP repeat domains of diap1, a domain implicated in binding REAPER, HID and GRIM [1].
  • The Drosophila inhibitor of apoptosis (IAP) DIAP2 is dispensable for cell survival, required for the innate immune response to gram-negative bacterial infection, and can be negatively regulated by the reaper/hid/grim family of IAP-binding apoptosis inducers [2].
  • Here, we generated synthetic Smac peptide which possesses an IAP-binding domain and Drosophila antennapaedia penetration sequence, and examined whether it enhances the effect of the chemotherapeutic agent etoposide in the human glioblastoma cell line [3].

High impact information on th

  • Drosophila IAP1 (DIAP1) is an endogenous caspase inhibitor that is crucial for regulating cell death during development [4].
  • We show that DmIKKvarepsilon promotes degradation of DIAP1 through direct phosphorylation [4].
  • Yorkie is known to activate Cyclin E (CycE) and the apoptosis inhibitor DIAP1 [5].
  • However, DmIKK epsilon-mediated degradation of DIAP1 does not regulate apoptosis as might be predicted but instead regulates actin dynamics, cell morphology, and the differentiation of sensory organ precursor cells [6].
  • Hpo phosphorylates and activates Wts, which in turn, through unknown mechanisms, negatively regulates the transcription of cell-cycle and cell-death regulators such as cycE and diap1 [7].

Biological context of th


Anatomical context of th


Associations of th with chemical compounds


Physical interactions of th

  • Mature Jafrac2 interacts genetically and biochemically with DIAP1 and promotes cell death in tissue culture cells and the Drosophila developing eye [17].
  • UBCD1 and Rpr specifically bind to DIAP1 and stimulate DIAP1 auto-ubiquitination in vitro [18].
  • This recognition is essential for DIAP1 binding to Dronc, and for targeting Dronc for ubiquitination [19].
  • Instead, a second IAP-binding domain, distinct from the R3, was identified at the C terminus of Reaper that bound to DIAP1 but failed to trigger apoptosis [20].

Enzymatic interactions of th


Regulatory relationships of th

  • Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms [10].
  • Silencing of diap1 or treatment with UV light induced DRONC processing, which occurred in two steps [22].
  • Here, we present an analysis of loss-of-function and gain-of-function alleles of th, which indicates that additional domains of TH/DIAP1 are necessary for its ability to inhibit death induced by RPR, GRIM, and HID [8].
  • Because loss of DIAP1 is sufficient to promote caspase activation, these mechanisms should promote apoptosis [10].
  • We conclude that D-IAP1 is capable of inhibiting the activation of drICE as well as inhibiting apoptosis induced by the active form of drICE [23].

Other interactions of th

  • Observations with Grim suggest that one mechanism by which these proteins produce a relative decrease in DIAP1 levels is to promote a general suppression of protein translation [10].
  • Co-silencing of dronc or dark largely suppressed this apoptosis, indicating that DIAP1 is normally required to inhibit an activity dependent on these proteins [22].
  • Our data suggest that DIAP1 instability, mediated through caspase activity and subsequent exposure of the N-end rule pathway, is essential for suppression of apoptosis [24].
  • It has been proposed that RPR, GRIM, and HID induce apoptosis by binding and inactivating TH/DIAP1 [8].
  • RNA interference studies in Drosophila embryos also demonstrated that the action of Dark is epistatic to that of DIAP1 in this cell death pathway [11].

Analytical, diagnostic and therapeutic context of th


  1. Induction of apoptosis by Drosophila reaper, hid and grim through inhibition of IAP function. Goyal, L., McCall, K., Agapite, J., Hartwieg, E., Steller, H. EMBO J. (2000) [Pubmed]
  2. The Drosophila inhibitor of apoptosis (IAP) DIAP2 is dispensable for cell survival, required for the innate immune response to gram-negative bacterial infection, and can be negatively regulated by the reaper/hid/grim family of IAP-binding apoptosis inducers. Huh, J.R., Foe, I., Muro, I., Chen, C.H., Seol, J.H., Yoo, S.J., Guo, M., Park, J.M., Hay, B.A. J. Biol. Chem. (2007) [Pubmed]
  3. Synthetic Smac peptide enhances the effect of etoposide-induced apoptosis in human glioblastoma cell lines. Mizukawa, K., Kawamura, A., Sasayama, T., Tanaka, K., Kamei, M., Sasaki, M., Kohmura, E. J. Neurooncol. (2006) [Pubmed]
  4. Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. Kuranaga, E., Kanuka, H., Tonoki, A., Takemoto, K., Tomioka, T., Kobayashi, M., Hayashi, S., Miura, M. Cell (2006) [Pubmed]
  5. The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila. Thompson, B.J., Cohen, S.M. Cell (2006) [Pubmed]
  6. A kinase gets caspases into shape. Montell, D.J. Cell (2006) [Pubmed]
  7. The Hippo signaling pathway coordinately regulates cell proliferation and apoptosis by inactivating Yorkie, the Drosophila Homolog of YAP. Huang, J., Wu, S., Barrera, J., Matthews, K., Pan, D. Cell (2005) [Pubmed]
  8. Diverse domains of THREAD/DIAP1 are required to inhibit apoptosis induced by REAPER and HID in Drosophila. Lisi, S., Mazzon, I., White, K. Genetics (2000) [Pubmed]
  9. The Drosophila caspase inhibitor DIAP1 is essential for cell survival and is negatively regulated by HID. Wang, S.L., Hawkins, C.J., Yoo, S.J., Müller, H.A., Hay, B.A. Cell (1999) [Pubmed]
  10. Hid, Rpr and Grim negatively regulate DIAP1 levels through distinct mechanisms. Yoo, S.J., Huh, J.R., Muro, I., Yu, H., Wang, L., Wang, S.L., Feldman, R.M., Clem, R.J., Müller, H.A., Hay, B.A. Nat. Cell Biol. (2002) [Pubmed]
  11. Down-regulation of DIAP1 triggers a novel Drosophila cell death pathway mediated by Dark and DRONC. Igaki, T., Yamamoto-Goto, Y., Tokushige, N., Kanda, H., Miura, M. J. Biol. Chem. (2002) [Pubmed]
  12. Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis. Wing, J.P., Schreader, B.A., Yokokura, T., Wang, Y., Andrews, P.S., Huseinovic, N., Dong, C.K., Ogdahl, J.L., Schwartz, L.M., White, K., Nambu, J.R. Nat. Cell Biol. (2002) [Pubmed]
  13. Anti- and pro-apoptotic activities of baculovirus and Drosophila IAPs in an insect cell line. Harvey, A.J., Soliman, H., Kaiser, W.J., Miller, L.K. Cell Death Differ. (1997) [Pubmed]
  14. A balance between the diap1 death inhibitor and reaper and hid death inducers controls steroid-triggered cell death in Drosophila. Yin, V.P., Thummel, C.S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  15. The Drosophila wing differentiation factor vestigial-scalloped is required for cell proliferation and cell survival at the dorso-ventral boundary of the wing imaginal disc. Delanoue, R., Legent, K., Godefroy, N., Flagiello, D., Dutriaux, A., Vaudin, P., Becker, J.L., Silber, J. Cell Death Differ. (2004) [Pubmed]
  16. Cleavage of the apoptosis inhibitor DIAP1 by the apical caspase DRONC in both normal and apoptotic Drosophila cells. Muro, I., Means, J.C., Clem, R.J. J. Biol. Chem. (2005) [Pubmed]
  17. Jafrac2 is an IAP antagonist that promotes cell death by liberating Dronc from DIAP1. Tenev, T., Zachariou, A., Wilson, R., Paul, A., Meier, P. EMBO J. (2002) [Pubmed]
  18. Regulation of Drosophila IAP1 degradation and apoptosis by reaper and ubcD1. Ryoo, H.D., Bergmann, A., Gonen, H., Ciechanover, A., Steller, H. Nat. Cell Biol. (2002) [Pubmed]
  19. Molecular mechanism of Reaper-Grim-Hid-mediated suppression of DIAP1-dependent Dronc ubiquitination. Chai, J., Yan, N., Huh, J.R., Wu, J.W., Li, W., Hay, B.A., Shi, Y. Nat. Struct. Biol. (2003) [Pubmed]
  20. Bifunctional killing activity encoded by conserved reaper proteins. Chen, P., Ho, S.I., Shi, Z., Abrams, J.M. Cell Death Differ. (2004) [Pubmed]
  21. Dissection of DIAP1 functional domains via a mutant replacement strategy. Yokokura, T., Dresnek, D., Huseinovic, N., Lisi, S., Abdelwahid, E., Bangs, P., White, K. J. Biol. Chem. (2004) [Pubmed]
  22. The Drosophila DIAP1 protein is required to prevent accumulation of a continuously generated, processed form of the apical caspase DRONC. Muro, I., Hay, B.A., Clem, R.J. J. Biol. Chem. (2002) [Pubmed]
  23. The Drosophila inhibitor of apoptosis D-IAP1 suppresses cell death induced by the caspase drICE. Kaiser, W.J., Vucic, D., Miller, L.K. FEBS Lett. (1998) [Pubmed]
  24. Degradation of DIAP1 by the N-end rule pathway is essential for regulating apoptosis. Ditzel, M., Wilson, R., Tenev, T., Zachariou, A., Paul, A., Deas, E., Meier, P. Nat. Cell Biol. (2003) [Pubmed]
  25. The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Pantalacci, S., Tapon, N., Léopold, P. Nat. Cell Biol. (2003) [Pubmed]
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