title: Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1alpha.
abstract: Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1alpha (TIF1alpha), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1alpha is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1alpha resemble those seen in mice carrying an activating mutation of the calcium sensor receptor (Casr) gene and, in TIF1alpha-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2, Cyp24a1, Trpv5, Trpv6, Calb1, S100g, Pthlh, and Spp1. Thus, our data indicate that TIF1alpha represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1alpha deficiency. Interestingly, the calcifying arteriopathy of TIF1alpha-null mutant mice shares features with the human age-related Mönckeberg's disease and, overall, the TIF1alpha-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ignat
authors.forename: Marius
authors.initials: M
authors.lastname: Teletin
authors.forename: Johan
authors.initials: J
authors.lastname: Tisserand
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khetchoumian
authors.forename: Christine
authors.initials: C
authors.lastname: Dennefeld
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Régine
authors.initials: R
authors.lastname: Losson
authors.forename: Manuel
authors.initials: M
authors.lastname: Mark
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001158:Arteries / Q000378:metabolism*; D002114:Calcinosis / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D014738:Vibrissae / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1; D002118:Calcium