E2F1 Of Apoptosis And ¦Â-catenin/TCF Pathway May

The E2F1 transcription factor regulates the expression of a large number of genes whose products are important for cell cycle progression, DNA synthesis, and mitosis. Unrestrained expression of E2F1 not only promotes S-phase entry but also induces apoptosis. Although it has been well documented that E2F1 is able to induce p53-dependent apoptosis via raising ARF activity, the mechanism by which E2F induces p53-independent apoptosis remains unclear.Here we report that E2F1 can directly bind to and activate the promoter of Smac/DIABLO, a mitochondrial proapoptotic gene, through the E2F1 binding sites BS2 (-542 ~ -535 bp) and BS3 (-200～-193 bp). BS2 and BS3 appear to be utilized in combination rather than singly by E2F1 in activation of Smac/DIABLO. Activation of BS2 and BS3 are E2F1 -specific, since neither E2F2 nor E2F3 is able to activate BS2 or BS3. Using the H1299 ER-E2F1 cell line where E2F1 activity can be conditionally induced, E2F1 is shown to upregulate the Smac/DIABLO expression at both mRNA and protein levels upon 4-hydroxytamoxifen (4-OHT) treatment, resulting in an enhanced mitochondria-mediated apoptosis. Reversely, reducing the Smac/DIABLO expression by RNA interference significantly diminishes apoptosis induced by E2F1. These results may suggest a novel mechanism by which E2F1 promotes p53-independent apoptosis through directly regulating its downstream mitochondrial apoptosis-inducing factors, such as Smac/DIABLO. Trascrpition factor E2F1 is the key regulator of cell proliferation and apoptosis. In healthy cells, E2F1 activity is strictly controlled by pRB/E2F pathway, which is frequently found mutated in most cancers. Also, E2F1 is reported to take a role in apoptosis. But it is less known what the crosstalks between E2F pathway with other crucial signal transduction pathways are.Here we demonstrate that E2F1 can directly bind to and activate the promoter of a ubiquitin ligase Siah1. The ectopic E2F1 can elevate Siah1 level. The Siah1 expression is reduced when endogenous E2F1 is repressed by shRNA. Ectopic E2F1 can depressβ-catenin/TCF activity, which is attenuated by the repression of endogenous Siah1 expression by shRNA. These results suggest that Siah1 is a bona fide E2F1 target gene and E2F1 can attenuate the activity ofβ-catenin/TCF pathway by upregulating Siah1 expression, which may imply a novel mutual restriction between the important pathways.