Details

Autor(en) / Beteiligte

• Dechat, Thomas
• Shimi, Takeshi
• Adam, Stephen A
• Rusinol, Antonio E
• Andres, Douglas A
• Spielmann, H. Peter
• Sinensky, Michael S
• Goldman, Robert D

Titel

Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2007-03, Vol.104 (12), p.4955-4960

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (LAΔ50/progerin). These modifications cause an abnormal association of LAΔ50/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 G₁ is impaired in cells expressing LAΔ50/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.