E2F1 death pathways as targets for cancer therapy

Abstract

Defects in apoptotic programs contribute to a number of human diseases, ranging from neurodegenerative disorders to malignancy, and treatment failure. The genetic basis for apoptosis implies that cell death can be disrupted by mutations, raising the intriguing possibility that cell numbers can be regulated by factors that influence cell survival. It is well documented that the E2F1 transcription factor is a key regulator of apoptotic programs. E2F1-induced cell death occurs via multiple pathways, some of which involve the tumour suppressor p53, and autonomous of p53. This has led to the opinion that E2F1 functions as a tumour surveillance factor, detecting aberrant proliferation and engaging apoptotic pathways to protect the organism from developing tumours. Frequently, novel players are discovered that expand the interpretation of apoptosis control by E2F1. This information will help to produce new strategies to exploit E2F1-induced apoptosis for therapeutic benefit.

1

During transition of cells from G1 to S phase, the activity of E2F is controlled by pRB, which binds E2F/DP, leading to transcriptional repression of E2F-responsive promoters in Go/G1. In late G1 pRB is phosphorylated by cyclin-dependent kinases (Cdk), which results in the release of E2F. Free E2F transactivates growth promoting genes such as cyclin E or cdc25A, resulting in S phase entry and cell cycle progression.

2

Mechanisms of E2F1-induced apoptosis. E2F1 promotes apoptosis via the tumour suppressor p53 and independent of p53. In the p53-dependent pathway, E2F1 activates ARF, which in turn stabilizes p53 by alleviating its proteosome degradation through Mdm2. ARF negatively regulates E2F1 in a feedback loop mechanism. In response to DNA damage E2F1 is stabilized through phosphorylation by ATM/ATR and Chk2 kinases (Chk2 also stabilizes p53 by phosphorylation). In addition, E2F1 interacts directly with p53 via the cyclin A binding domain, thereby inducing p53-mediated apoptosis. Alternatively, p53-independent apoptosis by E2F1 occurs via direct up-regulation of genes including p73 and Apaf-1. The assembly of Apaf1 with cytochrome c released from the mitochondria leads to formation of the apoptosome that catalyzes Caspase-9, and successive initiation of proapoptotic effector caspases including Caspase-3.

3

Spectrum of E2F1 apoptotic activities. E2F1 sensitizes cells to apoptosis by both direct activation of proapoptotic genes and through inhibition of antiapoptotic survival genes, thereby engaging different death signalling pathways via the mito-chondria (intrinsic), death receptors (extrinsic) and the endoplasmic reticulum.