Document Detail

Perturbation of wild-type lamin A metabolism results in a progeroid phenotype.
MedLine Citation:
PMID:  18363904     Owner:  NLM     Status:  MEDLINE    
Mutations in the lamin A/C gene cause the rare genetic disorder Hutchinson-Gilford progeria syndrome (HGPS). The prevalent mutation results in the production of a mutant lamin A protein with an internal 50 amino acid deletion which causes a cellular aging phenotype characterized by growth defects, limited replicative lifespan, and nuclear membrane abnormalities. However, the relevance of these findings to normal human aging is unclear. In this study, we demonstrate that increased levels of wild-type lamin A in normal human cells result in decreased replicative lifespan and nuclear membrane abnormalities that lead to apoptotic cell death and senescence in a manner that is strongly reminiscent of the phenotype shown by HGPS cells. In contrast to the accelerated aging defects observed in HGPS cells, the progeroid phenotype resulting from increased expression of wild-type lamin A can be rescued by overexpression of ZMPSTE24, the metalloproteinase responsible for the removal of the farnesylated carboxyl terminal region of lamin A. Furthermore, farnesyltransferase inhibitors also serve to reverse the progeroid phenotype resulting from increased lamin A expression. Significantly, cells expressing elevated levels of lamin A display abnormal lamin A localization and similar alterations in the nuclear distribution of lamin A are also observed in cells from old-age individuals. These data demonstrate that the metabolism of wild-type lamin A is delicately poised and even in the absence of disease-linked mutations small perturbations in this system are sufficient to cause prominent nuclear defects and result in a progeroid phenotype.
Jose Candelario; Sivasubramaniam Sudhakar; Sonia Navarro; Sita Reddy; Lucio Comai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-03-24
Journal Detail:
Title:  Aging cell     Volume:  7     ISSN:  1474-9726     ISO Abbreviation:  Aging Cell     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-05-15     Completed Date:  2008-10-06     Revised Date:  2014-10-22    
Medline Journal Info:
Nlm Unique ID:  101130839     Medline TA:  Aging Cell     Country:  England    
Other Details:
Languages:  eng     Pagination:  355-67     Citation Subset:  IM    
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MeSH Terms
Aged, 80 and over
Cell Aging
Cell Nucleus
Cells, Cultured
Genetic Vectors / genetics
Infant, Newborn
Lamin Type A / genetics,  metabolism*
Membrane Proteins / biosynthesis,  genetics
Metalloendopeptidases / biosynthesis,  genetics
Progeria / genetics*,  metabolism,  pathology
Grant Support
C06 CA62528/CA/NCI NIH HHS; C06 RR014514/RR/NCRR NIH HHS; C06 RR014514-01/RR/NCRR NIH HHS; C06 RR014514-01/RR/NCRR NIH HHS; C06 RR10600-01/RR/NCRR NIH HHS; F31 G076861//PHS HHS; R01 AG023873/AG/NIA NIH HHS
Reg. No./Substance:
0/Lamin Type A; 0/Membrane Proteins; EC 3.4.24.-/Metalloendopeptidases; EC protein, human

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