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Gene Review

rpr  -  reaper

Drosophila melanogaster

Synonyms: CG4319, Cell death protein rpr, Dmel\CG4319, Protein reaper, RPR, ...
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Disease relevance of rpr

  • Males mutant for rpr exhibited behavioral defects resulting in sterility [1].
  • In vivo binding studies demonstrated that both baculovirus and Drosophila IAPs physically interact with an apoptosis-inducing protein of Drosophila, Reaper (RPR), through their baculovirus IAP repeat (BIR) region [2].
  • Recently, amino acid sequence similarity was recognized between Drosophila Reaper and a protein known to be important for the replication and virulence of mosquito-borne bunyaviruses that cause human encephalitis [3].
  • Independent of caspase activation, Bunyavirus NSs proteins also share with Reaper the ability to directly inhibit cellular protein translation [4].
  • Halving the dosage of three cell death genes, rpr, grim, and hid, blocks shortening of the abdominal ganglion and induces neurodegeneration accompanied by accumulation of autofluorescent materials in the adult CNS [5].

High impact information on rpr

  • Dfd accomplishes this by directly activating the cell death promoting gene reaper (rpr) [6].
  • Here we show that HID blocks DIAP1's ability to inhibit caspase activity and provide evidence suggesting that RPR and GRIM can act similarly [7].
  • Decreased activity of this pathway enhances, and increased activity suppresses, apoptosis induced by ectopic expression of the cell death regulators reaper (rpr) and head involution defective (hid) [8].
  • Expression of the cell death regulatory protein REAPER (RPR) in the developing Drosophila eye results in a small eye owing to excess cell death [9].
  • To investigate whether rpr expression is sufficient to induce apoptosis, transgenic flies were generated that express rpr complementary DNA or the rpr open reading frame in cells that normally live [10].

Biological context of rpr


Anatomical context of rpr

  • Transient expression of rpr in the lepidopteran SF-21 cell line induced apoptosis displaying nuclear condensation and fragmentation, oligonucleosomal ladder formation, cell surface blebbing, and apoptotic body formation [15].
  • However, the central nervous systems of rpr null flies were very enlarged [1].
  • We show here that ecdysone-induced expression of the death activator genes reaper (rpr) and head involution defective (hid) is required for destruction of the larval midgut and salivary glands during metamorphosis, with hid playing a primary role in the salivary glands and rpr and hid acting in a redundant manner in the midguts [16].
  • These results establish that the Drosophila photoreceptors are sensitive to the rpr- and hid-driven cell death pathways [17].
  • reaper and bax initiate two different apoptotic pathways affecting mitochondria and antagonized by bcl-2 in Drosophila [18].

Associations of rpr with chemical compounds

  • Conversely, targeted expression of GlcT-1 partially rescued cell death caused by the proapoptotic factors Reaper and Grim, suggesting that ceramide generation might be one signal pathway that executes the cell death program [19].
  • This study reveals functional interactions between rpr and hid in Drosophila cell death responses and provides evidence that the precise timing of larval tissue cell death during metamorphosis is achieved through a steroid-triggered shift in the balance between the Drosophila inhibitor of apoptosis 1 and the rpr and hid death activators [16].
  • Ectopic expression of Reaper-C revealed cell killing activities distinct from full length Reaper, and indicated that the conserved NH2-terminal domain acts in part to modulate Reaper activity [20].
  • Induction of apoptosis by rpr overexpression or by cycloheximide or etoposide treatment of Drosophila cells results in proteolytic processing of drICE [21].
  • Apoptosis triggered by rpr required intracellular Ca(2+) ions and calmodulin [22].

Physical interactions of rpr

  • 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 [23].

Regulatory relationships of rpr

  • 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 [24].
  • Although both the ecdysone hormone receptor complex and p53 directly regulate rpr transcription, rpr was found to play a limited role in inducing apoptosis in response to either of these signals [1].
  • Loss of mir-14 enhances Reaper-dependent cell death, whereas ectopic expression suppresses cell death induced by multiple stimuli [25].

Other interactions of rpr

  • Here we show through a genetic screen that a mutant of Drosophila melanogaster tumour-necrosis factor receptor-associated factor 1 (DTRAF1) is a dominant suppressor of Reaper-induced cell death [26].
  • Mutations in the N-terminal region of Reaper, which displays sequence similarity to Hid and Grim, other Drosophila gene products correlated with the initiation of apoptosis, suggested that these residues might be functionally important [15].
  • It has been proposed that RPR, GRIM, and HID induce apoptosis by binding and inactivating TH/DIAP1 [24].
  • Inhibitors of ICE-family proteases p35 and crmA, as well as members of the iap class of genes, Op-iap and D-iap2, but not bcl-2 family members, blocked rpr-induced apoptosis [15].
  • JNK signaling acts upstream of both Reaper and effector caspases [27].

Analytical, diagnostic and therapeutic context of rpr

  • To elucidate the apoptotic signaling pathway, we have generated a cell culture model: S2 cells stably transfected with a Drosophila cell death gene, reaper (rpr) [22].
  • On the basis of sequence alignment data, it was recently proposed that RPR might represent an ancestral molecule from which the death domain in a number of proteins may have evolved [28].


  1. reaper is required for neuroblast apoptosis during Drosophila development. Peterson, C., Carney, G.E., Taylor, B.J., White, K. Development (2002) [Pubmed]
  2. Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs). Vucic, D., Kaiser, W.J., Harvey, A.J., Miller, L.K. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. Viral modulators of cell death provide new links to old pathways. Irusta, P.M., Chen, Y.B., Hardwick, J.M. Curr. Opin. Cell Biol. (2003) [Pubmed]
  4. Inhibition of translation and induction of apoptosis by Bunyaviral nonstructural proteins bearing sequence similarity to reaper. Colón-Ramos, D.A., Irusta, P.M., Gan, E.C., Olson, M.R., Song, J., Morimoto, R.I., Elliott, R.M., Lombard, M., Hollingsworth, R., Hardwick, J.M., Smith, G.K., Kornbluth, S. Mol. Biol. Cell (2003) [Pubmed]
  5. Pathology of the adult central nervous system induced by genetic inhibition of programmed cell death in Drosophila pupae. Usui-Aoki, K., Nakano, Y., Yamamoto, D. Arch. Insect Biochem. Physiol. (2002) [Pubmed]
  6. The Drosophila Hox gene deformed sculpts head morphology via direct regulation of the apoptosis activator reaper. Lohmann, I., McGinnis, N., Bodmer, M., McGinnis, W. Cell (2002) [Pubmed]
  7. 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]
  8. Ras promotes cell survival in Drosophila by downregulating hid expression. Kurada, P., White, K. Cell (1998) [Pubmed]
  9. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Hay, B.A., Wassarman, D.A., Rubin, G.M. Cell (1995) [Pubmed]
  10. Cell killing by the Drosophila gene reaper. White, K., Tahaoglu, E., Steller, H. Science (1996) [Pubmed]
  11. A steroid-triggered transcriptional hierarchy controls salivary gland cell death during Drosophila metamorphosis. Jiang, C., Lamblin, A.F., Steller, H., Thummel, C.S. Mol. Cell (2000) [Pubmed]
  12. 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]
  13. Steroid regulation of midgut cell death during Drosophila development. Lee, C.Y., Cooksey, B.A., Baehrecke, E.H. Dev. Biol. (2002) [Pubmed]
  14. Apoptosis in late stage Drosophila nurse cells does not require genes within the H99 deficiency. Foley, K., Cooley, L. Development (1998) [Pubmed]
  15. Characterization of reaper- and FADD-induced apoptosis in a lepidopteran cell line. Vucic, D., Seshagiri, S., Miller, L.K. Mol. Cell. Biol. (1997) [Pubmed]
  16. 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]
  17. Rpr- and hid-driven cell death in Drosophila photoreceptors. Hsu, C.D., Adams, S.M., O'Tousa, J.E. Vision Res. (2002) [Pubmed]
  18. reaper and bax initiate two different apoptotic pathways affecting mitochondria and antagonized by bcl-2 in Drosophila. Brun, S., Rincheval, V., Gaumer, S., Mignotte, B., Guenal, I. Oncogene (2002) [Pubmed]
  19. Drosophila glucosylceramide synthase: a negative regulator of cell death mediated by proapoptotic factors. Kohyama-Koganeya, A., Sasamura, T., Oshima, E., Suzuki, E., Nishihara, S., Ueda, R., Hirabayashi, Y. J. Biol. Chem. (2004) [Pubmed]
  20. Distinct cell killing properties of the Drosophila reaper, head involution defective, and grim genes. Wing, J.P., Zhou, L., Schwartz, L.M., Nambu, J.R. Cell Death Differ. (1998) [Pubmed]
  21. Identification of a Drosophila melanogaster ICE/CED-3-related protease, drICE. Fraser, A.G., Evan, G.I. EMBO J. (1997) [Pubmed]
  22. Participation of intracellular Ca(2+)/calmodulin and protein kinase(s) in the pathway of apoptosis induced by a Drosophila cell death gene, reaper. Piao, Z., Ui-Tei, K., Nagano, M., Miyata, Y. Mol. Cell Biol. Res. Commun. (2001) [Pubmed]
  23. Bifunctional killing activity encoded by conserved reaper proteins. Chen, P., Ho, S.I., Shi, Z., Abrams, J.M. Cell Death Differ. (2004) [Pubmed]
  24. 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]
  25. The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Xu, P., Vernooy, S.Y., Guo, M., Hay, B.A. Curr. Biol. (2003) [Pubmed]
  26. Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila. Kuranaga, E., Kanuka, H., Igaki, T., Sawamoto, K., Ichijo, H., Okano, H., Miura, M. Nat. Cell Biol. (2002) [Pubmed]
  27. Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. McEwen, D.G., Peifer, M. Development (2005) [Pubmed]
  28. Apoptotic activity of REAPER is distinct from signaling by the tumor necrosis factor receptor 1 death domain. Chen, P., Lee, P., Otto, L., Abrams, J. J. Biol. Chem. (1996) [Pubmed]
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