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Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition

Figure 3

FTI inhibition of prelamin A and progerin farnesylation and FTI-induced gene expression changes in fibroblasts from normal subjects.

(A) Western blot analysis of protein extracts of fibroblasts from individuals with HGPS and controls that were treated or untreated with FTI (1.5 µM lonafarnib daily for three days). Blots were probed with anti-lamin A/C (LA/C), anti-prelamin A (preLA), anti-actin, and anti HDJ-2 antibodies. Increase in levels of prelamin A and non-farnesylated HDJ-2 with FTI treatment are indicated. (B) 65 genes were differentially expressed in FTI-treated control cells. The signaling network was built upon functional association between protein farnesyltransferase (FTase), the enzymatic activity of which is inhibited by FTI, lamin A/C and Rb even though expression of all three transcripts remained unchanged with FTI treatment. Of note, lamin A is a known substrate for FTase. Downstream FTase interactions between all the 65 genes differentially expressed in FTI-treated control cells have been incorporated based on their interactions according to MetaCore analysis. The MetaCore analysis identified two transfactors, E2F1 and c-Myc, and one transfactor regulator, REP-1 that permit linking all those 65 genes into this single network. Symbols associating the genes functions are indicated. Genes labeled with blue circles were downregulated and by red circles were upregulated.

Figure 3