Proapoptotic activity of <i>Caenorhabditis elegans</i> CED-4 protein in <i>Drosophila</i> : Implicated mechanisms for caspase activation

  • Hirotaka Kanuka
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan
  • Shin Hisahara
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan
  • Kazunobu Sawamoto
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan
  • Shin-ichi Shoji
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan
  • Hideyuki Okano
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan
  • Masayuki Miura
    Department of Neuroanatomy, Biomedical Research Center, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan; Department of Neurology, Institute of Clinical Medical Sciences, University of Tsukuba, Tsukuba, 1-1-1 Tennoudai, Ibaraki 305-0006, Japan; and Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, 2-6-15 Shibakoen, Minato-ku, Tokyo 105-0011, Japan

抄録

<jats:p> CED-4 protein plays an important role in the induction of programmed cell death in <jats:italic>Caenorhabditis elegans</jats:italic> through the activation of caspases. However, the precise mechanisms by which it activates caspases remain unknown. To investigate the conservation of CED-4 function in evolution, transgenic <jats:italic>Drosophila</jats:italic> lines that express CED-4 in the compound eye were generated. Ectopic expression of CED-4 in the eyes induced massive apoptotic cell death through caspase activation. An ATP-binding site (P-loop) mutation in CED-4 (K165R) causes a loss of function in its ability to activate <jats:italic>Drosophila</jats:italic> caspase, and an ATPase inhibitor blocks the CED-4-dependent caspase activity in <jats:italic>Drosophila</jats:italic> S2 cells. Immunoprecipitation analysis showed that both CED-4 and CED-4 (K165R) bind directly to <jats:italic>Drosophila</jats:italic> caspase drICE, and the overexpression of CED-4 (K165R) inhibits CED-4-, ecdysone-, or cycloheximide-dependent caspase activation in S2 cells. Furthermore, CED-4 (K165R) partially prevented cell death induced by CED-4 in <jats:italic>Drosophila</jats:italic> compound eyes. Thus, CED-4 function is evolutionarily conserved in <jats:italic>Drosophila</jats:italic> , and the molecular mechanisms by which CED-4 activates caspases might require ATP binding and direct interaction with the caspases. </jats:p>

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