Life and death decisions by the E2F transcription factors

Abstract

The E2F transcription factors are critical regulators of genes required for appropriate progression through the cell cycle, and in special circumstances they can also promote the expression of another class of genes that function in the apoptotic program. Since E2Fs can initiate both cell proliferation and cell death, it is not surprising that the pro-apoptotic capacity of these proteins is subject to complex regulation. Recent study has expanded our knowledge of the factors influencing E2F-induced apoptosis as well as downstream targets of E2F in this process.

Figure 1. The E2F Family of Transcription Factors

The E2F family is divided into three groups based on their structure and function. All E2Fs contain a homologous DNA-binding domain (red). The “activating E2Fs” E2F1, E2F2, and E2F3a each contain both a nuclear localization signal (NLS, blue) and a transactivation/pocket protein-binding domain (purple). The “repressive E2Fs” lack the N-terminal domain present in the activating E2Fs, and E2F4 and E2F5 accordingly lack NLS sequences. E2F6, E2F7, and E2F8 lack sequences required for transactivation and pocket protein-binding, and therefore are pocket protein-independent repressors of transcription.

Figure 2. Regulation of cell cycle-dependent transcription by the pRB-E2F pathway

E2F target genes are regulated by repression of transcription in G₀/G₁ phase, followed by activation in G₁/S phase. Repressive complexes containing primarily E2F4 and p107/p130 occupy promoters in G₀/G₁ phase, and association with chromatin remodeling enzymes such as histone deacetylases (HDAC) contributes to transcriptional repression. pRB binds to and inhibits the transcriptional activity of the activating E2Fs 1-3. Upon cell cycle entry, cyclin-CDK complexes such as cyclin D-CDK4 overcome inhibition by CDK inhibitors such as p16^INK4a and phosphorylate the pocket proteins. This phosphorylation leads to disruption of the pocket protein-E2F complexes, causing E2F4 to be exported from the nucleus, and activating E2Fs to bind the promoters of cell cycle-regulated target genes and activate their transcription.

Figure 3. Complex regulation of E2F and p53 in the apoptotic response pathway

Many proteins regulate the activity of E2F and p53 in the apoptotic response. In turn, E2F and p53 transcriptionally activate a large number of pro-apoptotic genes. Transcriptional targets of E2F are shown in red; targets of p53 are shown in blue; targets of both E2F and p53 are indicated in purple.