Human papillomavirus type 16 E7 oncoprotein binds and inactivates growth-inhibitory insulin-like growth factor binding protein 3

The E7 protein encoded by human papillomavirus type 16 is one of the few vi ral genes that can immortalize primary human cells and thereby override cel lular senescence. While it is generally assumed that this property of E7 de pends on its interaction with regulators of the cell cycle, we show here th at E7 targets insulin-like growth factor binding protein 3 (IGFBP-3), the p roduct of a p53-inducible gene that is overexpressed in senescent cells. IG FBP-3 can suppress cell proliferation and induce apoptosis; we show here th at IGFBP-3-mediated apoptosis is inhibited by E7, which binds to IGFBP-3 an d triggers its proteolytic cleavage. Two transformation-deficient mutants o f E7 failed to inactivate IGFBP-3, suggesting that inactivation of IGFBP-3 may contribute to cell transformation.