The cellular transcription factor E2F, previously identified as a component of early adenovirus transcription, has now been shown to be important in cell proliferation control. E2F appears to be a functional target for the action of the tumor suppressor protein Rb that is encoded by the retinoblastoma susceptibility gene. The disruption of this E2F-Rb interaction, as well as a complex involving E2F in association with the cell cycle-regulated cyclin A-cdk2 kinase complex, may be a common mechanism of action for the oncoproteins encoded by the DNA tumor viruses.

https://science.sciencemag.org/content/sci/258/5081/424.full.pdf

E2F: a link between the Rb tumor suppressor protein and viral oncoproteins

The retinoblastoma protein copurifies with E2F-I, an E1A-regulated inhibitor of the transcription factor E2F

https://www.cell.com/cell/pdf/0092-8674(91)90019-U.pdf

Cell cycle regulation of the E2F transcription factor involves an interaction with cyclin A

https://www.cell.com/cell/pdf/0092-8674(90)90112-R.pdf

Adenovirus E1A proteins can dissociate heteromeric complexes involving the E2F transcription factor: A novel mechanism for E1A trans-activation

The E2F transcription factor is found in complexes with a variety of cellular proteins including the retinoblastoma tumor suppressor protein. Various assays have demonstrated a tight correlation between the functional capacity of Rb as a growth suppressor and its ability to bind to E2F. Moreover, only the underphosphorylated form of Rb, which appears to be the active species, interacts with E2F. Despite the fact that the majority of Rb becomes hyperphosphorylated at the end of G1, we now show that the E2F-Rb interaction persists through the G1/S transition and into S phase. A distinct E2F complex does appear to be regulated in relation to the transition from G1 to S phase. We now demonstrate that this complex contains the Rb-related p107 protein. Moreover, like the Rb protein, p107 inhibits E2F-dependent transcription in a co-transfection assay. This result, together with the observation that free, uncomplexed E2F accumulates as cells leave G1 and enter S phase, suggests that the p107 protein may regulate E2F-dependent transcription during G1. In contrast, although Rb does regulate the transcriptional activity of E2F, this association does not coincide with the G1 to S phase transition.

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1993.tb05742.x

Interactions of the p107 and Rb proteins with E2F during the cell proliferation response.

Previous experiments have demonstrated that adenovirus infection of human and mouse cells leads to an E1A-dependent activation of the DNA-binding capacity of a cellular transcription factor termed E2F. E2F binds to two sites in the adenovirus E2 early promoter which have been shown to be critical for E1A-dependent E2 early transcription, and the E2F-binding sites can confer E1A-induced transcription to a heterologous promoter. In addition, under a variety of circumstances, the increase in E2F-binding activity coincides with the activation of E2 transcription. We now find that, in addition to the E1A gene, another early viral gene, the E4 gene, is necessary for the activation of E2F-binding activity. Extracts prepared from human 293 cells, which express the E1A and E1B genes, had low levels of E2F activity, whereas infection of 293 cells with the E1A mutant dl312 increased E2F activity. This increase did not occur when 293 cells were infected with dl366, an E4 deletion mutant, nor was there an increase in E2F activity in HeLa cells infected with either dl366 or dl312; however, a coinfection with the two mutants yielded the normal wild-type increase in E2F. Furthermore, infection of HeLa cells with a high multiplicity of dl312, conditions that allow E4 gene expression in the absence of E1A, did not yield an increase in E2F activity. Thus, it appears that both the E1A gene and the E4 gene are directly involved in E2F activation. Measurements of E2 RNA production in a dl366 infection as compared with a wild-type or dl312 infection demonstrate that the E4 gene is essential for full E2 transcription. Furthermore, transfection assays of the E2 promoter demonstrate that, although E1A alone can trans-activate the E2 promoter, it is not as effective as the combination of E1A and E4 in the induction of the E2 promoter. We therefore conclude that the activation of the E2F factor leading to the activation of E2 transcription requires the combined action of both the E1A 289-amino-acid protein and an E4 product.

M C Simon

Papers

The adenovirus E4 gene, in addition to the E1A gene, is important for trans-activation of E2 transcription and for E2F activation.