Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway

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. T...

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Veröffentlicht in:Oncotarget 2017-05, Vol.8 (21), p.34045-34056
Hauptverfasser: Kinoshita, Daisuke, Nagasawa, Ayako, Shimizu, Ippei, Ito, Takashi K, Yoshida, Yohko, Tsuchida, Masanori, Iwama, Atsushi, Hayano, Toshiya, Minamino, Tohru
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Sprache:eng
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Zusammenfassung: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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.15973