The eight “E2F*_targets” modules correspond to the gene targets of the eight E2F transcription factors. The three transcription factors E2F1, 2 and 3, though not having well-documented differences at the level of protein-protein interactions and represented by a generic entity in our diagram, show their specifics at the transcription level. For this reason, the generic entity is decomposed into the three individual components in the upper part of the diagram.
According to our diagram, RB/E2F pathway is a self-regulating molecular mechanism as there exist multiple positive and negative feedbacks through transcription: among the 79 proteins described in the diagram, 23 are targets of the E2Fs transcription factors, both activators and inhibitors. More specifically, E2F1, E2F6, E2F7 and E2F8 transcription factors have their own genes as targets, creating several positive feedback controls that may serve for stabilizing the behavior of the whole RB/E2F pathway activity.
To analyze the differences between the E2Fs and their roles in other contexts, we calculated the significance of the overlaps of all E2F1-8 transcriptional targets with other known pathways such as MSigDB database (BROAD, MIT). As expected, these lists have highly significant overlaps with cell-cycle, G1/S transition, Rb/E2F, or p21-related pathways. Some other overlaps highlight the involvement of RB/E2F in some differentiation-related pathways and reciprocally. However, only E2F1 target list is linked to various apoptosis-related pathways (APOPTOSIS_GENMAP. APOPTOSIS_KEGG, DEATH_PATHWAY and others). In particular, E2F1, but not the other E2Fs, targets p53 tumor suppressor gene in RB/E2F pathway. This confirms the recent findings that E2F1 is the only specific inducer of apoptosis among the E2F transcription factors, even though its level can be regulated by other E2Fs (Lazzerini Denchi and Helin, 2005). In our diagram, E2F1 is a target gene for all E2Fs with the exception of E2F5.
Click here for interactive version of E2F1 target genes
Click here for interactive version of E2F2 target genes
Click here for interactive version of E2F3 target genes
Click here for interactive version of E2F4 target genes
Click here for interactive version of E2F5 target genes
Click here for interactive version of E2F6 target genes
Click here for interactive version of E2F7 target genes
Click here for interactive version of E2F8 target genes
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