Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment.
Cell Mol Life Sci
; 62(22): 2669-78, 2005 Nov.
Article
em En
| MEDLINE
| ID: mdl-16261260
ABSTRACT
Hutchinson-Gilford progeria (HGPS) is a premature aging syndrome associated with LMNA mutations. Progeria cells bearing the G608G LMNA mutation are characterized by accumulation of a mutated lamin A precursor (progerin), nuclear dysmorphism and chromatin disorganization. In cultured HGPS fibroblasts, we found worsening of the cellular phenotype with patient age, mainly consisting of increased nuclear-shape abnormalities, progerin accumulation and heterochromatin loss. Moreover, transcript distribution was altered in HGPS nuclei, as determined by different techniques. In the attempt to improve the cellular phenotype, we applied treatment with drugs either affecting protein farnesylation or chromatin arrangement. Our results show that the combined treatment with mevinolin and the histone deacetylase inhibitor trichostatin A dramatically lowers progerin levels, leading to rescue of heterochromatin organization and reorganization of transcripts in HGPS fibroblasts. These results suggest that morpho-functional defects of HGPS nuclei are directly related to progerin accumulation and can be rectified by drug treatment.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Progéria
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Heterocromatina
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Inibidores de Hidroximetilglutaril-CoA Redutases
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Ácidos Hidroxâmicos
Limite:
Child
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Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article