Trans-activation of the adenovirus E2 promoter by human papillomavirus type 16 E7 is mediated by retinoblastoma-dependent and -independent pathways

Abstract

In common with the adenovirus E1A and simian virus 40 large T oncoproteins, the E7 protein of human papiUomavirus (HPV) type 16 interacts with the retinoblastoma (Rb) tumour suppressor protein (pRb). The functional importance of this interaction for protein was investigated by analysis of the transactivating function of E7 at the adenovirus E2 promoter in a set of breast tumour cell lines. Trans-activation by HPV-16 E7 in two pRb-deficient cell lines demonstrated that pRb is not essential for E7-mediated transactivation, but reconstitution of Rb expression indicated the existence of an Rb-mediated pathway of E7 transactivation. This pathway results from suppression by E7 of a trans-repressing function encoded by the Rb gene. The E7 protein is shown to be capable of interacting in vivo with the Rb-related protein p107. Furthermore, analysis of a fusion construct between the amino terminus of Rb and the carboxy terminus of p107 suggests that, in common with pRb, the p107 protein trans-represses the adenovirus E2 early promoter.Therefore it is proposed that the pRb-independent pathway of E7 trans-activation is a consequence of the suppression of trans-repression by p107.

The human papillomavirus type 16 E7 protein complements adenovirus type 5 E1A amino-terminus-dependent transactivation of adenovirus type 5 early genes and increases ATF and Oct-1 DNA binding activity

“…We show here that other transcription factors besides E2F which induce Ad5 early gene transcription can be regulated by the E1A amino terminus. This is consistent with findings from studies of HPV E7 that show that binding RB is not essential for inducing adenovirus E2 gene expression (17,48). These results also indirectly support the hypothesis that additional factors besides RB, such as p107 and p130, whose binding is unaffected by the deletions outside CR2 in the E1A amino terminus, regulate E2F.…”

“…HPV18 and the related HPV16 belong to a class of papillomaviruses whose infections are highly correlated with the genesis of cervical malignancies (95). The E7 protein of HPV16 provides transactivation, transformation, and host protein binding activities similar to those of E1A (17,22,60,61,71,72). Like E1A, the HPV E7 protein binds the RB protein (22,26,27).…”

Comparison of the properties of the E6 and E7 genes of low- and high-risk cutaneous papillomaviruses reveals strongly transforming and high Rb-binding activity for the E7 protein of the low-risk human papillomavirus type 1

“…This may indicate that these proteins, when bound to Rb, interfere with E2F binding more extensively than HPV1 E7 does. Alternatively, activation of the AdE2 promoter could be mediated through disruption of the p107-E2F complex (6,44). The high Rbbinding affinity of CRPV E7 observed by others with a truncated in vitro-translated Rb protein (18) additionally suggests that sequences outside the core E7 binding site on Rb influence Rb-E7 interactions.…”

Cellular transformation by human papillomaviruses: Lessons learned by comparing high- and low-risk viruses

“…High-risk HPV E7 binds the other Rb family members, p107 and p130, and point mutations within the LXCXE motif show that high-risk HPV E7 is able to distinguish between Rb family members (Carlotti and Crawford, 1993; Ciccolini et al, 1994; Davies et al, 1993). Low-risk HPV E7 binds the Rb family members with lower affinity (Demers et al, 1996; Gage et al, 1990; Munger et al, 1989b).…”