Research Papers: Gerotarget (Focus on Aging):

Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes

Ray Kreienkamp, Monica Croke, Martin A. Neumann, Gonzalo Bedia-Diaz, Simona Graziano, Adriana Dusso, Dale Dorsett, Carsten Carlberg and Susana Gonzalo _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:30018-30031. https://doi.org/10.18632/oncotarget.9065

Metrics: PDF 2859 views  |   HTML 3907 views  |   ?  


Ray Kreienkamp1, Monica Croke1, Martin A. Neumann1, Gonzalo Bedia-Diaz1, Simona Graziano1, Adriana Dusso3, Dale Dorsett1, Carsten Carlberg2 and Susana Gonzalo1

1 Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University School of Medicine, St. Louis, MO, USA

2 School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland

3 Bone and Mineral Research Unit, 
Hospital Universitario Central de Asturias, Oviedo, Spain

Correspondence to:

Susana Gonzalo, email:

Keywords: DNA repair, genomic instability, laminopathies, progeria, vitamin D receptor, Gerotarget

Received: January 26, 2016 Accepted: April 16, 2016 Published: April 27, 2016


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 9065