title: Mammalian dap3 is an essential gene required for mitochondrial homeostasis in vivo and contributing to the extrinsic pathway for apoptosis.
abstract: Death-associated protein-3 (DAP3) is a GTP binding protein previously implicated in both intramitochondrial protein synthesis and apoptosis. To explore the in vivo roles of DAP3, we generated and characterized DAP3-deficient mice. Homozygous dap3-/- embryos died at approximately day 9.5 in utero. The dap3-/- embryos and placentas were markedly shrunken. Embryos had arrested development, displaying severe growth restriction and lack of axial turning. Transmission electron microscopy analysis revealed abnormal, shrunken mitochondria with swollen crystae in dap3-/- embryos. Levels of cytochrome c oxidase-I, a protein encoded in the mitochondrial genome, were reduced in dap3-/- embryos, consistent with a role for DAP3 in intramitochondrial protein synthesis. A requirement for DAP3 in mitochondrial respiration was also revealed by oxygen consumption measurements using cultured cells treated with DAP3-specific small interfering RNA (siRNA). Studies of cultured cells from dap3-/- embryos confirmed a role in apoptosis induced by stimuli that trigger the extrinsic (TNFalpha, TRAIL, anti-Fas antibody) but not intrinsic (mitochondrial) cell death pathway. Thus, DAP3 joins a growing list of bifunctional proteins that play roles in normal mitochondrial physiology and in apoptosis.
authors.affiliation: Burnham Institute for Medical Research, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Hyung-Ryong
authors.initials: HR
authors.lastname: Kim
authors.forename: Han-Jung
authors.initials: HJ
authors.lastname: Chae
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Anna
authors.initials: A
authors.lastname: Monosov
authors.forename: Edward
authors.initials: E
authors.lastname: Monosov
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D005260:Female; D020043:Genes, Essential; D005804:Genes, Lethal; D006367:HeLa Cells; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D011247:Pregnancy; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; C490762:Dap3 protein, mouse; D011506:Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins