Research Papers: Gerotarget (Focus on Aging):
Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway
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Daisuke Kinoshita1,2, Ayako Nagasawa2,3, Ippei Shimizu2,4, Takashi K. Ito1, Yohko Yoshida2,4, Masanori Tsuchida3, Atsushi Iwama5, Toshiya Hayano6 and Tohru Minamino2
1 Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
2 Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
3 Department of Thoracic and Cardiovascular Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
4 Division of Molecular Aging and Cell Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
5 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
6 Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Shiga, Japan
Tohru Minamino, email:
Keywords: cellular senescence, HGPS, DNA-PK, vascular smooth muscle cells, p53, Gerotarget
Received: October 10, 2016 Accepted: February 28, 2017 Published: March 07, 2017
Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK). In contrast, wild-type lamin A and lamin A mutants causing atypical Werner syndrome were able to bind to these molecules. We also found that forced expression of progerin in vascular smooth muscle cells led to activation of DNA-PK and cellular growth arrest, while knockdown of DNA-PK attenuated this. Deletion of p53 also improved the inhibition of cell growth due to forced expression of progerin. These findings suggested that progerin activates the DNA damage response pathway and that dysregulation of this pathway may be responsible for the development of cardiovascular pathology in patients with HGPS.
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