title: PrP(c) deficiency and dasatinib protect mouse intestines against radiation injury by inhibiting of c-Src.
abstract: Despite extensive study of the contribution of cell death and apoptosis to radiation-induced acute intestinal injury, our knowledge of the signaling mechanisms involved in epithelial barrier dysfunction remains inadequate. Because PrP(c) plays a key role in intestinal homeostasis by renewing epithelia, we sought to study its role in epithelial barrier function after irradiation.
  
  
  
  Histology, morphometry and plasma FD-4 levels were used to examine ileal architecture, wound healing, and intestinal leakage in PrP(c)-deficient (KO) and wild-type (WT) mice after total-body irradiation. Impairment of the PrP(c) Src pathway after irradiation was explored by immunofluorescence and confocal microscopy, with Caco-2/Tc7 cells. Lastly, dasatinib treatment was used to switch off the Src pathway in vitro and in vivo.
  
  
  
  The decrease in radiation-induced lethality, improved intestinal wound healing, and reduced intestinal leakage promoted by PrP(c) deficiency demonstrate its involvement in acute intestinal damage. Irradiation of Cacao2/Tc7 cells induced PrP(c) to target the nuclei associated with Src activation. Finally, the protective effect triggered by dasatinib confirmed Src involvement in radiation-induced acute intestinal toxicity.
  
  
  
  Our data are the first to show a role for the PrP(c)-Src pathway in acute intestinal response to radiation injury and offer a novel therapeutic opportunity.
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Strup-Perrot
authors.affiliation: Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France; Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France; Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Monceau
authors.affiliation: Institut Curie, Translational Research Department, Hopital St Louis, Paris, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Pouzoulet
authors.affiliation: Laboratoire de Radio-Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Service Commun d'Expérimentation Animale, Institut Gustave Roussy, Villejuif, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Petit
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Holler
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Institut de Recherche Clinique Animale, Maisons-Alfort Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Perrot
authors.affiliation: Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Institut de Recherche Clinique Animale, Maisons-Alfort Cedex, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Desquibert
authors.affiliation: Stéphane FOUQUET, Centre de Recherche Institut de la Vision, UMR_S968 Inserm/UPMC/CHNO des Quinze-Vingts, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fouquet
authors.affiliation: CNRS, UMR-8122, Institut Gustave Roussy, Villejuif, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquere
authors.affiliation: CNRS, UMR-8122, Institut Gustave Roussy, Villejuif, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Rousset
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France; Ecole Pratique des Hautes Etudes, Laboratoire de Pharmacologie Cellulaire et Moléculaire, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thenet
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, France; INSERM, U 872, Paris, France; Université Paris Descartes-Paris 5, UMR S 872, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cardot
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, SRBE, Laboratoire de Recherche sur la Régénération des tissus sains Irradiés, Fontenay-aux-Roses, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.affiliation: Inserm U1030, Radiotherapie experimentale, Institut Gustave Roussy, Villejuif, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
authors.affiliation: Institut de Radioprotection et de Sûreté Nucléaire, PRP-HOM, Fontenay-aux-Roses, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Aigueperse
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D018938:Caco-2 Cells; D000069439:Dasatinib / Q000627:therapeutic use*; D006801:Humans; D007422:Intestines / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072002:Prion Proteins / Q000172:deficiency* / Q000502:physiology; D011832:Radiation Injuries / Q000517:prevention & control*; D014916:Whole-Body Irradiation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000072002:Prion Proteins; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D000069439:Dasatinib
keywords: Intestinal wound healing; Irradiation; Mouse model; Permeability