Amyloid Precursor Protein Binding Protein Fe65 Is Cleaved by Caspases during DNA Damage-Induced Apoptosis

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  • Saeki Kazunori
    Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science
  • Nose Yasuyo
    Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science
  • Hirao Nobukuni
    Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science
  • Takasawa Ryoko
    Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science
  • Tanuma Sei-ichi
    Department of Biochemistry, Faculty of Pharmaceutical Science, Tokyo University of Science Genome and Drug Research Center, Tokyo University of Science

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Caspases cleave several cellular proteins to execute cell death by apoptosis. The identification of novel substrates of caspases could provide an important clue for elucidation of new apoptosis signaling pathways. In this study, we tested whether an amyloid precursor protein (APP) binding protein Fe65 is proteolytically degraded in neuronal cell death by apoptosis, using a neuron-like cell line, human neuroblastoma SH-SY5Y cells. When treated with DNA damaging agents, etoposide (ETP) and camptothecin (CPT), SH-SY5Y cells underwent apoptosis in a dose-dependent manner. Interestingly, Fe65 (97 kDa) was cleaved to a 65 kDa product during DNA damage-induced apoptosis. Furthermore, the cleavage of Fe65 was accompanied by activation of caspases-9 and -3. The restriction cleavage of Fe65 was completely suppressed by the treatment with a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe) fluoromethylketone (z-VAD-fmk). These results reveal the restriction cleavage of Fe65 by caspases during DNA damage-induced apoptosis. Since Fe65 has been shown to suppress APP processing to amyloid β (Aβ) production, our findings may provide a new insight into the molecular mechanism by which DNA damage induces Aβ production and subsequent neuronal cell death in Alzheimer's disease (AD).

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