Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 May 1;17(9):2526–2533. doi: 10.1093/emboj/17.9.2526

CIDE, a novel family of cell death activators with homology to the 45 kDa subunit of the DNA fragmentation factor.

N Inohara 1, T Koseki 1, S Chen 1, X Wu 1, G Núñez 1
PMCID: PMC1170594  PMID: 9564035

Abstract

DFF45 is a subunit of the DNA fragmentation factor (DFF) that is cleaved by caspase-3 during apoptosis. However, the mechanism by which DFF45 regulates apoptotic cell death remains poorly understood. Here we report the identification and characterization of two mammalian genes, CIDE-A and CIDE-B, encoding highly related proteins with homology to the N-terminal region of DFF45. CIDE-A and CIDE-B were found to activate apoptosis in mammalian cells, which was inhibited by DFF45 but not by caspase inhibitors. Expression of CIDE-A induced DNA fragmentation in 293T cells, which was inhibited by DFF45, further suggesting that DFF45 inhibits the apoptotic activities of CIDEs. In addition to mammalian CIDE-A and CIDE-B, we identified DREP-1, a Drosophila melanogaster homolog of DFF45 that could inhibit CIDE-A-mediated apoptosis. Mutant analysis revealed that the C-terminal region of CIDE-A was necessary and sufficient for killing whereas the region with homology to DFF45 located in the N-terminus was required for DFF45 to inhibit CIDE-A-induced apoptosis. CD95/Fas-mediated apoptosis was enhanced by CIDEs but inhibited by DFF45. These studies suggest that DFF45 is evolutionarily conserved and implicate CIDEs as DFF45-inhibitable effectors that promote cell death and DNA fragmentation.

Full Text

The Full Text of this article is available as a PDF (443.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alnemri E. S., Livingston D. J., Nicholson D. W., Salvesen G., Thornberry N. A., Wong W. W., Yuan J. Human ICE/CED-3 protease nomenclature. Cell. 1996 Oct 18;87(2):171–171. doi: 10.1016/s0092-8674(00)81334-3. [DOI] [PubMed] [Google Scholar]
  2. An B., Dou Q. P. Cleavage of retinoblastoma protein during apoptosis: an interleukin 1 beta-converting enzyme-like protease as candidate. Cancer Res. 1996 Feb 1;56(3):438–442. [PubMed] [Google Scholar]
  3. Casciola-Rosen L. A., Miller D. K., Anhalt G. J., Rosen A. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J Biol Chem. 1994 Dec 9;269(49):30757–30760. [PubMed] [Google Scholar]
  4. Chinnaiyan A. M., O'Rourke K., Lane B. R., Dixit V. M. Interaction of CED-4 with CED-3 and CED-9: a molecular framework for cell death. Science. 1997 Feb 21;275(5303):1122–1126. doi: 10.1126/science.275.5303.1122. [DOI] [PubMed] [Google Scholar]
  5. Cohen G. M. Caspases: the executioners of apoptosis. Biochem J. 1997 Aug 15;326(Pt 1):1–16. doi: 10.1042/bj3260001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Danesch U., Hoeck W., Ringold G. M. Cloning and transcriptional regulation of a novel adipocyte-specific gene, FSP27. CAAT-enhancer-binding protein (C/EBP) and C/EBP-like proteins interact with sequences required for differentiation-dependent expression. J Biol Chem. 1992 Apr 5;267(10):7185–7193. [PubMed] [Google Scholar]
  7. Enari M., Sakahira H., Yokoyama H., Okawa K., Iwamatsu A., Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature. 1998 Jan 1;391(6662):43–50. doi: 10.1038/34112. [DOI] [PubMed] [Google Scholar]
  8. Inohara N., Ding L., Chen S., Núez G. harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L). EMBO J. 1997 Apr 1;16(7):1686–1694. doi: 10.1093/emboj/16.7.1686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Inohara N., Koseki T., Hu Y., Chen S., Núez G. CLARP, a death effector domain-containing protein interacts with caspase-8 and regulates apoptosis. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10717–10722. doi: 10.1073/pnas.94.20.10717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jacobson M. D., Weil M., Raff M. C. Programmed cell death in animal development. Cell. 1997 Feb 7;88(3):347–354. doi: 10.1016/s0092-8674(00)81873-5. [DOI] [PubMed] [Google Scholar]
  11. Lazebnik Y. A., Kaufmann S. H., Desnoyers S., Poirier G. G., Earnshaw W. C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994 Sep 22;371(6495):346–347. doi: 10.1038/371346a0. [DOI] [PubMed] [Google Scholar]
  12. McCarthy N. J., Whyte M. K., Gilbert C. S., Evan G. I. Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol. 1997 Jan 13;136(1):215–227. doi: 10.1083/jcb.136.1.215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. doi: 10.1016/s0092-8674(00)81874-7. [DOI] [PubMed] [Google Scholar]
  14. Nicholson D. W., Ali A., Thornberry N. A., Vaillancourt J. P., Ding C. K., Gallant M., Gareau Y., Griffin P. R., Labelle M., Lazebnik Y. A. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37–43. doi: 10.1038/376037a0. [DOI] [PubMed] [Google Scholar]
  15. Numa F., Hirabayashi K., Tsunaga N., Kato H., O'Rourke K., Shao H., Stechmann-Lebakken C., Varani J., Rapraeger A., Dixit V. M. Elevated levels of syndecan-1 expression confer potent serum-dependent growth in human 293T cells. Cancer Res. 1995 Oct 15;55(20):4676–4680. [PubMed] [Google Scholar]
  16. Sakahira H., Enari M., Nagata S. Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature. 1998 Jan 1;391(6662):96–99. doi: 10.1038/34214. [DOI] [PubMed] [Google Scholar]
  17. Song Q., Lees-Miller S. P., Kumar S., Zhang Z., Chan D. W., Smith G. C., Jackson S. P., Alnemri E. S., Litwack G., Khanna K. K. DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis. EMBO J. 1996 Jul 1;15(13):3238–3246. [PMC free article] [PubMed] [Google Scholar]
  18. Spector M. S., Desnoyers S., Hoeppner D. J., Hengartner M. O. Interaction between the C. elegans cell-death regulators CED-9 and CED-4. Nature. 1997 Feb 13;385(6617):653–656. doi: 10.1038/385653a0. [DOI] [PubMed] [Google Scholar]
  19. Thompson C. B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995 Mar 10;267(5203):1456–1462. doi: 10.1126/science.7878464. [DOI] [PubMed] [Google Scholar]
  20. Wang X., Pai J. T., Wiedenfeld E. A., Medina J. C., Slaughter C. A., Goldstein J. L., Brown M. S. Purification of an interleukin-1 beta converting enzyme-related cysteine protease that cleaves sterol regulatory element-binding proteins between the leucine zipper and transmembrane domains. J Biol Chem. 1995 Jul 28;270(30):18044–18050. doi: 10.1074/jbc.270.30.18044. [DOI] [PubMed] [Google Scholar]
  21. White E. Life, death, and the pursuit of apoptosis. Genes Dev. 1996 Jan 1;10(1):1–15. doi: 10.1101/gad.10.1.1. [DOI] [PubMed] [Google Scholar]
  22. Williams P. M., Chang D. J., Danesch U., Ringold G. M., Heller R. A. CCAAT/enhancer binding protein expression is rapidly extinguished in TA1 adipocyte cells treated with tumor necrosis factor. Mol Endocrinol. 1992 Jul;6(7):1135–1141. doi: 10.1210/mend.6.7.1508226. [DOI] [PubMed] [Google Scholar]
  23. Wu D., Wallen H. D., Inohara N., Nuñez G. Interaction and regulation of the Caenorhabditis elegans death protease CED-3 by CED-4 and CED-9. J Biol Chem. 1997 Aug 22;272(34):21449–21454. doi: 10.1074/jbc.272.34.21449. [DOI] [PubMed] [Google Scholar]
  24. Wu D., Wallen H. D., Nuñez G. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science. 1997 Feb 21;275(5303):1126–1129. doi: 10.1126/science.275.5303.1126. [DOI] [PubMed] [Google Scholar]
  25. Xiang J., Chao D. T., Korsmeyer S. J. BAX-induced cell death may not require interleukin 1 beta-converting enzyme-like proteases. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14559–14563. doi: 10.1073/pnas.93.25.14559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Zou H., Henzel W. J., Liu X., Lutschg A., Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997 Aug 8;90(3):405–413. doi: 10.1016/s0092-8674(00)80501-2. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES