title: Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage.
abstract: Fe65 interacts with the cytosolic domain of the Alzheimer amyloid precursor protein (APP). The functions of the Fe65 are still unknown. To address this point we generated Fe65 knockout (KO) mice. These mice do not show any obvious phenotype; however, when fibroblasts (mouse embryonic fibroblasts), isolated from Fe65 KO embryos, were exposed to low doses of DNA damaging agents, such as etoposide or H2O2, an increased sensitivity to genotoxic stress, compared with wild type animals, clearly emerged. Accordingly, brain extracts from Fe65 KO mice, exposed to non-lethal doses of ionizing radiations, showed high levels of gamma-H2AX and p53, thus demonstrating a higher sensitivity to X-rays than wild type mice. Nuclear Fe65 is necessary to rescue the observed phenotype, and few minutes after the exposure of MEFs to DNA damaging agents, Fe65 undergoes phosphorylation in the nucleus. With a similar timing, the proteolytic processing of APP is rapidly affected by the genotoxic stress: in fact, the cleavage of the APP COOH-terminal fragments by gamma-secretase is induced soon after the exposure of cells to etoposide, in a Fe65-dependent manner. These results demonstrate that Fe65 plays an essential role in the response of the cells to DNA damage.
authors.affiliation: CEINGE Biotecnologie Avanzate, 80145 Napoli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Minopoli
authors.forename: Maria
authors.initials: M
authors.lastname: Stante
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.forename: Francesca
authors.initials: F
authors.lastname: Telese
authors.forename: Luigi
authors.initials: L
authors.lastname: Aloia
authors.forename: Mario
authors.initials: M
authors.lastname: De Felice
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Lauro
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
authors.forename: Arturo
authors.initials: A
authors.lastname: Brunetti
authors.forename: Nicola
authors.initials: N
authors.lastname: Zambrano
authors.forename: Tommaso
authors.initials: T
authors.lastname: Russo
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001921:Brain / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D000972:Antineoplastic Agents, Phytogenic; C486243:Apbb1 protein, mouse; D006657:Histones; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D016159:Tumor Suppressor Protein p53; C475961:gamma-H2AX protein, mouse; D005047:Etoposide; D006861:Hydrogen Peroxide