title: Tripartite motif 24 (Trim24/Tif1α) tumor suppressor protein is a novel negative regulator of interferon (IFN)/signal transducers and activators of transcription (STAT) signaling pathway acting through retinoic acid receptor α (Rarα) inhibition.
abstract: Recent genetic studies in mice have established that the nuclear receptor coregulator Trim24/Tif1α suppresses hepatocarcinogenesis by inhibiting retinoic acid receptor α (Rara)-dependent transcription and cell proliferation. However, Rara targets regulated by Trim24 remain unknown. We report that the loss of Trim24 resulted in interferon (IFN)/STAT pathway overactivation soon after birth (week 5). Despite a transient attenuation of this pathway by the induction of several IFN/STAT pathway repressors later in the disease, this phenomenon became more pronounced in tumors. Remarkably, Rara haplodeficiency, which suppresses tumorigenesis in Trim24(-/-) mice, prevented IFN/STAT overactivation. Moreover, together with Rara, Trim24 bound to the retinoic acid-responsive element of the Stat1 promoter and repressed its retinoic acid-induced transcription. Altogether, these results identify Trim24 as a novel negative regulator of the IFN/STAT pathway and suggest that this repression through Rara inhibition may prevent liver cancer.
authors.affiliation: Department of Functional Genomics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP 10142, 67404 Illkirch-Cedex, Communauté Urbaine de Strasbourg, France.
authors.forename: Johan
authors.initials: J
authors.lastname: Tisserand
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khetchoumian
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembélé
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D016000:Cluster Analysis; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015203:Reproducibility of Results; D000072482:Retinoic Acid Receptor alpha; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D009687:Nuclear Proteins; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D050791:STAT Transcription Factors; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1; D014212:Tretinoin; D007372:Interferons