Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging.
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.
Dechat
Thomas
T
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Shimi
Takeshi
T
Adam
Stephen A
SA
Rusinol
Antonio E
AE
Andres
Douglas A
DA
Spielmann
H Peter
HP
Sinensky
Michael S
MS
Goldman
Robert D
RD
D000375:Aging / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D016193:G1 Phase; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D034921:Lamin Type B / Q000378:metabolism; D008745:Methylation; D008938:Mitosis; D050505:Mutant Proteins / Q000378:metabolism*; D034881:Nuclear Lamina / Q000378:metabolism; D011371:Progeria / Q000473:pathology; D017368:Protein Prenylation; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D034904:Lamin Type A; D034921:Lamin Type B; D050505:Mutant Proteins; D011993:Recombinant Fusion Proteins