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  E2F1 and c-Myc Potentiate Apoptosis through Inhibition of NF-kB Activity that Facilitates MnSOD-mediated ROS Elimination



Both c-Myc and E2F1 are critical transcriptional factors for G1/S transition. Although their overexpression is coupled with abnormal growth of malignant cells, it can also enhance apoptosis in some culture conditions. However, its mechanism remains unknown. Here, we found that overexpressed E2F1 and c-Myc potentiated serum-deprived apoptosis in NIH3T3 cells. In these cells, the expression of MnSOD was disrupted due to the lack of NF-κB activities during serum deprivation, which led to ROS (reactive oxygen species)-mediated apoptosis. As for this mechanism, we found that E2F1 inhibited NF-κB activities by binding to its subunit p65. We transfected mutant E2F1s (as shown in Fig.A) together with a marker gene, red fluorescent protein (DsRed), and detected apoptotic cells with Annexin V-EGFP after 48-h serum deprivation. Mutant E2F1 122-243 that lacks the transactivating domain but can inhibit NF-κB activities enhanced serum-deprived apoptosis as efficiently as wild type (WT) E2F1, while 122-243/E132 that can not bind to p65 was scarcely effective (B). This result indicates that E2F1 potentiates apoptosis by binding to p65 independently of its transcriptional activities. In addition, we found that endogeneous E2F1 released from Rb during G1/S transition inhibited NF-κB activities.

These results indicate that proliferating cells are susceptible to apoptosis due to the suppressed NF-κB activities by E2F1.


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