Defective Lamin A-Rb Signaling in Hutchinson-Gilford Progeria Syndrome and Reversal by Farnesyltransferase Inhibition
The main network (center left) shows downstream interactions between lamin A/C and the 352 differentially expressed genes in HGPS fibroblasts. The network was built using MetaCore analyses, which finds known interactions between gene products. (A) The network divides into several distinct regions, the main region being the regulatory and signaling network. (B) The detailed view of the main region (top right) shows that the only gene differentially expressed in HGPS directly downstream of lamin A/C (layer 1) is that encoding Rb (layer 2). In turn, most of the immediate downstream partners of Rb included in this dataset are p107, NCOA2, SP1, and ATF-2 and E2F1 (layer 3). Of the remaining genes that occur downstream of layer 3, nearly half of the 280 genes interact with only one or more of these transfactors associated to the main network (center left); these gene products are placed above the centre. From layer 4 and 5, most of the genes can be connected at least to one entity according to GeneGO. In the HGPS dataset, 124 genes that had no known interactions in GeneGO are not shown. From the center regulatory and signaling network (zoom left, panel B)), several groups of genes segregate into six subnetworks, based on mutual interactions: a group denoted DNA repair (bottom left, panel (C)), motility (bottom right, panel (D)), and three circles of genes regulated by E2F1, ATF-2 and SP1, respectively. Symbols associating the genes with functions are indicated. Genes labeled with blue circles were downregulated and red circles were upregulated. Higher magnifications of panels A to D are provided in Figures S1, S2, S3 and S4.