Kuganesan Nishanth, Dlamini Samkeliso, Hasan Safiyyah, Viranga Tillekeratne L M, Taylor William R
Department of Biological Sciences, University of Toledo, 2801 W. Bancroft Street, MS 601, Toledo, OH, 43606, USA.
Department of Medicinal and Biological Chemistry, University of Toledo, 2801 W. Bancroft Street, MS 601, Toledo, OH, 43606, USA.
Biochimie. 2025 Jun 25;236:127-137. doi: 10.1016/j.biochi.2025.06.013.
The E2F family of transcription factors plays multiple roles in cell cycle regulation. E2F can be inhibited by binding to RB proteins, an interaction that is regulated by CDK phosphorylation of RB. We previously observed that CDKs, RB, and E2F regulate ferroptosis, a type of programmed cell death characterized by catastrophic peroxidation of membrane lipids. Here we investigate the impact of E2F on ferroptosis. E2F1 regulates both pro and anti-ferroptotic proteins including ALOX5, MYC, SLC7A11, ATF4, and GPX4 and finally renders a net inhibitory role in ferroptosis. Interestingly, we also obtained evidence for a cell type dependent compensatory effect of E2F3 upon E2F1 depletion. Specifically, downregulation of ferroptotic genes upon E2F1 knockdown fails to occur in an osteosarcoma cell line which upregulates E2F3 under these conditions. Taken together, our study identifies a number of E2F targets with the potential to affect ferroptotic sensitivity.
转录因子E2F家族在细胞周期调控中发挥多种作用。E2F可通过与RB蛋白结合而被抑制，这种相互作用受RB的CDK磷酸化调节。我们之前观察到，CDK、RB和E2F调节铁死亡，这是一种程序性细胞死亡，其特征是膜脂发生灾难性过氧化。在此，我们研究E2F对铁死亡的影响。E2F1调节促铁死亡和抗铁死亡蛋白，包括ALOX5、MYC、SLC7A11、ATF4和GPX4，最终在铁死亡中发挥净抑制作用。有趣的是，我们还获得了证据，表明在E2F1缺失时，E2F3具有细胞类型依赖性的补偿作用。具体而言，在骨肉瘤细胞系中，E2F1敲低后铁死亡基因的下调并未发生，在这些条件下该细胞系会上调E2F3。综上所述，我们的研究确定了一些可能影响铁死亡敏感性的E2F靶点。
