Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor

Abstract

The transforming proteins of several DNA tumour viruses, including adenovirus E1a and simian virus 40 large T antigen, complex with the retinoblastoma (Rb) tumour-suppressor gene product. This requires regions in these viral proteins necessary for transformation and is thought to inactivate the growth-suppressing properties of the Rb protein by disrupting its interaction with cellular targets. Indeed, regions of Rb required to form a complex with E1a and large T antigen are often mutated in transformed cells. The level at which the Rb protein regulates proliferation is unknown, although one possibility is transcription. We have previously characterized a sequence-specific transcription factor, DRTF1, the activity of which is downregulated as embryonal carcinoma stem cells differentiate. DRTF1 is found in several discrete protein complexes (a, b and c) which are of different sizes but have the same DNA specificity. We now show that one of these also contains the Rb protein and, further, that the adenovirus E1a protein causes the dissociation of the Rb protein from this complex. This requires conserved regions 1 and 2 of E1a that are known to be required for efficient transformation. These results demonstrate that the Rb protein forms a complex with a DNA-bound transcription factor, and suggests that the Rb protein might act by regulating transcription.

Nuclear protein phosphorylation and growth control

“…At least seven cellular proteins can complex with pRB in vitro (Kaelin etal., 1991;Huang etal., 1991), including the transcription factors c-Myc (Rustgi et al, 1991) and E2F (Bandara & La Thangue, 1991;Chellappan et al, 1991;Bagchi et al, 1991;Chittenden et al, 1991). pRB is therefore thought to act as a transcriptional repressor by sequestering key proteins which are required for cell cycle progression (Wagner & Green, 1991).…”

Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule

“…pRb phosphorylation takes place at a time point in the later part of the G1 phase that coincides with the restriction point of the cell cycle in which the cells commit themselves to replicate DNA (Pardee, 1989;Geng and Weinberg, 1993). The mitogen induced phosphorylation of pRb by CDK-cyclin D kinases releases the E2F transcription factor from pRb which leads to the induction of gene products that are essential for the cells to commence DNA replication (Bandara and La Thangue, 1991;Chellappan et al, 1991;Neveins, 1992;La Thangue, 1994). The release of E2F also ensures that pRb remains in a hyperphosphorylated state by a feed back induction of cyclin E expression which together with cdk2 keeps pRb inactive in an mitogen independent fashion (Weinberg, 1995;Sherr, 1996).…”

E2F-1 regulation by an unusual DNA damage-responsive DP partner subunit

“…1,2 The first member of the family to be identified, E2F-1, is a crucial target of the retinoblastoma (pRb) tumour suppressor protein in the control of the G1-to S-phase transition. 3,4 pRb physically interacts with DNAbound E2F-1 and thereby prevents transcriptional activity. 5 In turn, cell cycle progression cannot occur, which is important for pRb to exert its tumour suppressor activity.…”