Apaf-1 is a transcriptional target for E2F and p53

Loss of function of the retinoblastoma protein, pRB, leads to lack of diffe rentiation, hyperproliferation and apoptosis. Inactivation of pRB results i n deregulated E2F activity, which in turn induces entry to S-phase and apop tosis. Induction of apoptosis by either the loss of pRB or the deregulation of E2F activity occurs via both p53-dependent and p53-independent mechanis ms. The mechanism by which E2F induces apoptosis is still unclear. Here we show that E2F1 directly regulates the expression of Apaf-1, the gene for ap optosis protease-activating factor 1. These results provide a direct link b etween the deregulation of the pRB pathway and apoptosis. Furthermore, beca use the pRB pathway is functionally inactivated in most cancers, the identi fication of Apaf-1 as a transcriptional target for E2F might explain the in creased sensitivity of tumour cells to chemotherapy. We also show that, ind ependently of the pRB pathway, Apaf-1 is a direct transcriptional target of p53, suggesting that p53 might sensitize cells to apoptosis by increasing Apaf-1 levels.