| Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. | |
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MedLine Citation:
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PMID: 21715679 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS. |
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Authors:
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Kan Cao; John J Graziotto; Cecilia D Blair; Joseph R Mazzulli; Michael R Erdos; Dimitri Krainc; Francis S Collins |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Science translational medicine Volume: 3 ISSN: 1946-6242 ISO Abbreviation: Sci Transl Med Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-30 Completed Date: 2011-10-25 Revised Date: 2013-01-31 |
Medline Journal Info:
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Nlm Unique ID: 101505086 Medline TA: Sci Transl Med Country: United States |
Other Details:
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Languages: eng Pagination: 89ra58 Citation Subset: IM |
Affiliation:
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Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-8004, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibiotics, Antineoplastic / pharmacology* Autophagy / drug effects Cell Nucleus / drug effects, ultrastructure Cells, Cultured Fibroblasts / cytology, drug effects*, metabolism* HeLa Cells Humans Lamin Type A / genetics, metabolism Nuclear Proteins / genetics, metabolism Phenotype* Progeria / metabolism*, pathology, physiopathology Protein Precursors / genetics, metabolism Recombinant Fusion Proteins / genetics, metabolism Sirolimus / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R00 AG029761/AG/NIA NIH HHS; R00AG029761/AG/NIA NIH HHS; R01NS051303/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Lamin Type A; 0/Nuclear Proteins; 0/Protein Precursors; 0/Recombinant Fusion Proteins; 0/prelamin A; 53123-88-9/Sirolimus |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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