Dynamics of lamin-A processing following precursor accumulation.
Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed.
Liu
Qian
Q
Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong, China.
Kim
Dae In
DI
Syme
Janet
J
LuValle
Phyllis
P
Burke
Brian
B
Roux
Kyle J
KJ
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D053140:Organelle Shape / Q000187:drug effects; D010641:Phenotype; D054876:Prenylation / Q000187:drug effects; D011371:Progeria / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013997:Time Factors
D017320:HIV Protease Inhibitors; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A