FLASH protein is a component of death-inducing signaling complex and might be involved in death receptor-mediated extrinsic apoptosis. Here we developed the peptide aptamer against death effecter domain recruiting domain (DRD) of FLASH protein and showed that the peptide bound to FLASH protein in vitro. Intracellular expression of the DRD-binding peptide aptamer specifically suppressed receptor-mediated extrinsic apoptosis but not intrinsic pathway, which was recapitulated by the antisense oligonucleotides for FLASH. These data. suggest that DRD-binding peptide is not only a novel inhibitor modulating receptor-mediated apoptosis but also a tool for elucidating the roles of FLASH ill apoptosis. (c) 2006 Elsevier Inc. All rights reserved.