E2F-1 DP-1 INDUCES P53 AND OVERRIDES SURVIVAL FACTORS TO TRIGGER APOPTOSIS/

The E2F DNA binding activity consists of a heterodimer between E2F and DP family proteins, and these interactions are required for associati on of E2F proteins with pRb and the pRb-related proteins p107 and p130 , which modulate E2F transcriptional activities. E2F-1 expression is s ufficient to release fibroblasts from G(0) and induce entry into S pha se, yet it also initiates apoptosis. To investigate the mechanisms of E2F-induced apoptosis, we utilized interleukin-3 (IL-3)-dependent 32D. 3 myeloid cells, a model of hematopoietic progenitor programmed cell d eath. In the absence of IL-3, E2F-1 alone was sufficient to induce apo ptosis, and p53 levels were diminished. DP-1 alone was not sufficient to induce cell cycle progression or alter rates of death following IL- 3 withdrawal. However, overexpression of both E2F-1 and DP-1 led to th e rapid death of cells even in the presence of survival factors. In th e presence of IL-3, levels of endogenous wild-type p53 increased in re sponse to E2F-1, and coexpression of DP-1 further augmented p53 levels . These results provide evidence that E2F is a functional link between the tumor suppressors p53 and pRb. However, induction of p53 alone wa s not sufficient to trigger apoptosis, suggesting that the ability of E2F to override survival factors involves additional effectors.