Cleavage of E2F‐1‐regulating proteins and activation of E2F‐1 during CD95‐induced death of thymocytes

Summary The CD95 death receptor activates caspases that cleave a variety of intracellular substrates, including cell cycle control proteins. However, the significance of this cleavage for the induction of apoptosis is unclear. In this study, CD95‐induced cleavage of the G1/S checkpoint regulator proteins, retinoblastoma protein (pRb) and murine‐double‐minute‐2 (mdm‐2), was associated with an increased protein concentration of a key transcription factor, E2F‐1, which is regulated by both of them. Furthermore, DNA‐binding activity to E2F sites is increased. In thymocytes, CD95‐induced apoptosis was associated with increased E2F‐1 DNA‐binding activity, while thymocytes that lacked E2F‐1 were less susceptible to CD95‐induced apoptosis. We conclude that the G1/S checkpoint is an important target of CD95 signalling. CD95‐activated caspases cleave regulator proteins to increase E2F‐1 activity, and inappropriate activation of E2F‐1 is part of the mechanism of CD95‐induced apoptosis.