Apoptotic action of E2F1 requires glycogen synthase kinase 3-beta activity in PC12 cells. Espada Lilia,Udapudi Basavaraj,Podlesniy Petar,Fabregat Isabel,Espinet Carme,Tauler Albert Journal of neurochemistry Both E2F1 and GSK3beta have been described as essential targets in neuronal apoptosis. Previous studies have demonstrated that GSK3beta binds to E2F1 in vivo. We wanted to investigate whether these proteins could share a common apoptotic signal pathway in neuronal cells. With this intention, we developed a PC12 ER-E2F1 stable cell line in which E2F1 activity was dependent on the presence of 4-hydroxitamoxifen. E2F1 activation produced apoptosis in naive and post-mitotic cells; serum and nerve growth factor respectively protected them from E2F1 apoptotic stimuli. The presence of specific GSK3beta inhibitors SB216763 and LiCl completely protected cells from apoptosis induced by E2F1 activation. In addition, knocked down GSK3beta experiments by small interference RNAs have demonstrated that a reduction of GSK3beta protein levels can lower the apoptotic effect of E2F1. Finally, we demonstrated that the apoptotic effect of E2F1 is not due to the regulation of GSK3beta activity, and that the inhibitory effect of GSK3beta inhibitor SB216763 on E2F1 induced apoptosis could be due to an alteration in the E2F1-regulated transcription gene pattern. In summary, we have demonstrated that the apoptotic action of E2F1 requires GSK3beta activity. 10.1111/j.1471-4159.2007.04686.x

Phosphofructokinases Axis Controls Glucose-Dependent mTORC1 Activation Driven by E2F1. Almacellas Eugènia,Pelletier Joffrey,Manzano Anna,Gentilella Antonio,Ambrosio Santiago,Mauvezin Caroline,Tauler Albert iScience Cancer cells rely on mTORC1 activity to coordinate mitogenic signaling with nutrients availability for growth. Based on the metabolic function of E2F1, we hypothesize that glucose catabolism driven by E2F1 could participate on mTORC1 activation. Here, we demonstrate that glucose potentiates E2F1-induced mTORC1 activation by promoting mTORC1 translocation to lysosomes, a process that occurs independently of AMPK activation. We showed that E2F1 regulates glucose metabolism by increasing aerobic glycolysis and identified the PFKFB3 regulatory enzyme as an E2F1-regulated gene important for mTORC1 activation. Furthermore, PFKFB3 and PFK1 were found associated to lysosomes and we demonstrated that modulation of PFKFB3 activity, either by substrate accessibility or expression, regulates the translocation of mTORC1 to lysosomes by direct interaction with Rag B and subsequent mTORC1 activity. Our results support a model whereby a glycolytic metabolon containing phosphofructokinases transiently interacts with the lysosome acting as a sensor platform for glucose catabolism toward mTORC1 activity. 10.1016/j.isci.2019.09.040