title: Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes.
abstract: Hutchinson-Gilford Progeria Syndrome (HGPS) is a devastating incurable premature aging disease caused by accumulation of progerin, a toxic lamin A mutant protein. HGPS patient-derived cells exhibit nuclear morphological abnormalities, altered signaling pathways, genomic instability, and premature senescence. Here we uncover new molecular mechanisms contributing to cellular decline in progeria. We demonstrate that HGPS cells reduce expression of vitamin D receptor (VDR) and DNA repair factors BRCA1 and 53BP1 with progerin accumulation, and that reconstituting VDR signaling via 1α,25-dihydroxyvitamin D3 (1,25D) treatment improves HGPS phenotypes, including nuclear morphological abnormalities, DNA repair defects, and premature senescence. Importantly, we discovered that the 1,25D/VDR axis regulates LMNA gene expression, as well as expression of DNA repair factors. 1,25D dramatically reduces progerin production in HGPS cells, while stabilizing BRCA1 and 53BP1, two key factors for genome integrity. Vitamin D/VDR axis emerges as a new target for treatment of HGPS and potentially other lamin-related diseases exhibiting VDR deficiency and genomic instability. Because progerin expression increases with age, maintaining vitamin D/VDR signaling could keep the levels of progerin in check during physiological aging.
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Kreienkamp
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Croke
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Neumann
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Bedia-Diaz
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Simona
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Dorsett
authors.affiliation: School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Carsten
authors.initials: C
authors.lastname: Carlberg
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D015536:Down-Regulation; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D034881:Nuclear Lamina / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D061251:Primary Cell Culture; D011371:Progeria / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D014815:Vitamins / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C400134:BAP1 protein, human; D034904:Lamin Type A; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C579457:VDR protein, human; D014815:Vitamins; C090764:prelamin A; D043222:Ubiquitin Thiolesterase; D002117:Calcitriol
keywords: DNA repair; Gerotarget; genomic instability; laminopathies; progeria; vitamin D receptor