Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.
Marji
Jackleen
J
Department of Dermatology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
O'Donoghue
Seán I
SI
McClintock
Dayle
D
Satagopam
Venkata P
VP
Schneider
Reinhard
R
Ratner
Desiree
D
Worman
Howard J
HJ
Gordon
Leslie B
LB
Djabali
Karima
K
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D019084:Fluorescent Antibody Technique, Indirect; D055106:Genome-Wide Association Study; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011371:Progeria / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D034904:Lamin Type A; D016160:Retinoblastoma Protein; D051231:Farnesyltranstransferase