Abstract
Inactivation of the tumor suppressor pRB by the human papillomavirus (HPV) oncoprotein E7 is a mechanism by which HPV promotes cell growth. The bovine papillomavirus type 1 (BPV-1) E7 does not bind pRB efficiently yet is required for full transformation of murine cells by BPV-1. In the present study, we investigated the mechanism of BPV-1 E7-induced cell proliferation. Our studies indicate that expression of BPV-1 E7 induces DNA synthesis and stimulates cells to enter S phase in quiescent cells. The induction of cell proliferation by BPV-1 E7 can occur in the retinoblastoma gene (Rb)-null cells, suggesting an Rb-independent mechanism. Consistent with this observation, BPV-1 E7 does not efficiently activate the transcription of the E2F family of transcription factors (E2F)-responsive promoters. Notably, c-Myc is able to induce cells to enter S phase in quiescent cells through an Rb/E2F-independent pathway. Significantly, c-Myc levels are increased in BPV-1 E7-expressing cells. Moreover, expression of a dominant negative c-Myc mutant inhibited BPV-1 E7-induced DNA synthesis. Consistent with the notion that c-Myc could down-regulate p27 and activate Cdk2, p27 level is decreased while both cyclin A and cyclin E-associated kinase activities are up-regulated in BPV-1 E7-expressing cells. These studies indicate an important role for c-Myc in BPV-1 E7-induced cell proliferation.
Highlights
Type for studies of molecular biology of the papillomaviruses
The bovine papillomavirus type 1 (BPV-1) E7 does not bind pRB efficiently yet is required for full transformation of murine cells by BPV-1
Inactivation of the tumor suppressor pRB by the human papillomavirus (HPV) E7 is a mechanism by which HPV promotes cell growth. pRB-independent biological activities of E7 have been observed, but the precise mechanism for these E7 functions are not well understood
Summary
Type for studies of molecular biology of the papillomaviruses (for review, see Ref. 1). The E7 proteins of both the low and high risk HPVs were able to activate the Ad E2 promoter (6 – 8). The ability of E7 protein to associate with and destabilize the cellular tumor suppressor pRB has been suggested as a mechanism by which the viral protein promotes cell proliferation (Ref. 9 and references therein). Inactivation of pRB leads to activation of cellular genes driven by the E2F transcription factor that are important for S phase entry in mammalian cells (reviewed in Ref. 10). PRB-independent biological activities of E7 have been observed and multiple additional cellular interactors of the viral proteins have been identified (for review, see Ref. 3). The sequences in the C-terminal half of E7 proteins are well conserved between BPV-1 and HPVs. A low affinity pRB-binding site has been identified from the C terminus of HPV-16 E7 [22]. We have demonstrated a low affinity association of BPV-1 E7 protein with pRB but not p107 [18]
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