Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging.
Proc Natl Acad Sci U S A
; 104(12): 4955-60, 2007 Mar 20.
Article
em En
| MEDLINE
| ID: mdl-17360326
ABSTRACT
Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson-Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the mutant LA (LADelta50/progerin). These modifications cause an abnormal association of LADelta50/progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G(1) is impaired in cells expressing LADelta50/progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
/
Lamina Tipo A
/
Proteínas Mutantes
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Mitose
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article