Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts
Kan Cao, … , Elizabeth G. Nabel, Francis S. Collins
Kan Cao, … , Elizabeth G. Nabel, Francis S. Collins
Published June 13, 2011
Citation Information: J Clin Invest. 2011;121(7):2833-2844. https://doi.org/10.1172/JCI43578.
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Research Article Aging

Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts

Abstract

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.

Authors

Kan Cao, Cecilia D. Blair, Dina A. Faddah, Julia E. Kieckhaefer, Michelle Olive, Michael R. Erdos, Elizabeth G. Nabel, Francis S. Collins

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Figure 3

Immortalized cells suppress progerin transcription.

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Immortalized cells suppress progerin transcription. (A) Schematic re...
(A) Schematic representation of the positions of progerin- or lamin A– specific primers used for RT-PCR analysis. (B) qRT-PCR. Primary lines included normal fibroblast cell lines HGFDFN168 and HGFDFN090 (Fb1 and Fb2, respectively); human aortic SMC line; and B lymphocyte lines AG09393 and AG11659 (BL1 and BL2, respectively). HGPS fibroblast lines were HGADFN167 and HGADFN003 (HGPS1 and HGPS2, respectively). 4 immortalized lines of indicated cell types are also shown. qRT-PCR showed more progerin mRNA than LMNA mRNA in HGPS cell lines, which was an artifact caused by the difference in priming efficiency of progerin-and lamin A–specific primers (see Supplemental Figure 4C). (C) Representative images of quantitative telomere PNA-FISH analysis of human TERT–immortalized (+TERT) and primary (–TERT) fibroblast cells (AG09838, p8). DNA was stained with DAPI in blue to show the boundary of the nucleus (outlines), and telomere-FISH signals are in green. (D) qRT-PCR analysis of the total progerin mRNA amount in normal and human TERT–immortalized cell lines with progerin-specific primers. The relative expression values for progerin were normalized to the mean values of endogenous LMNA. HeLa and 293T lines are shown as controls.