title: The TGF-β/Smad repressor TG-interacting factor 1 (TGIF1) plays a role in radiation-induced intestinal injury independently of a Smad signaling pathway.
abstract: Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-β/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the present study, we hypothesized that TGF-β1 signaling and target genes expression may depend on radiation-induced modifications in Smad transcriptional co-repressors/inhibitors expressions (TGIF1, SnoN, Ski and Smad7). In endothelial cells (HUVECs) and in a model of experimental radiation enteropathy in mice, radiation exposure increases expression of TGF-β/Smad pathway and of its target gene PAI-1, together with the overexpression of Smad co-repressor TGIF1. In mice, TGIF1 deficiency is not associated with changes in the expression of radiation-induced TGF-β pathway-related transcripts following localized small intestinal irradiation. In HUVECs, TGIF1 overexpression or silencing has no influence either on the radiation-induced Smad activation or the Smad3-dependent PAI-1 overexpression. However, TGIF1 genetic deficiency sensitizes mice to radiation-induced intestinal damage after total body or localized small intestinal radiation exposure, demonstrating that TGIF1 plays a role in radiation-induced intestinal injury. In conclusion, the TGF-β/Smad co-repressor TGIF1 plays a role in radiation-induced normal tissue damage by a Smad-independent mechanism.
authors.affiliation: Laboratory of Radiopathology and Experimental Therapies, Institute for Radiological Protection and Nuclear Safety (IRSN), Fontenay-aux-Roses, France.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hneino
authors.forename: Agnes
authors.initials: A
authors.lastname: François
authors.forename: Valerie
authors.initials: V
authors.lastname: Buard
authors.forename: Georges
authors.initials: G
authors.lastname: Tarlet
authors.forename: Rym
authors.initials: R
authors.lastname: Abderrahmani
authors.forename: Karl
authors.initials: K
authors.lastname: Blirando
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hoodless
authors.forename: Marc
authors.initials: M
authors.lastname: Benderitter
authors.forename: Fabien
authors.initials: F
authors.lastname: Milliat
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C051321:SERPINE1 protein, human; C512653:Ski protein, mouse; C486157:Skil protein, mouse; D051785:Smad Proteins; D051906:Smad7 Protein; C508961:Tgfb1 protein, mouse; C490797:Tgif1 protein, mouse; D053773:Transforming Growth Factor beta1; C060614:SKI protein, human