Human Papillomavirus Type 16 E7 Oncoprotein Binds and Inactivates Growth-Inhibitory Insulin-Like Growth Factor Binding Protein 3

Abstract

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

ACKNOWLEDGMENTS

We are grateful to Gerald Pfister for expert assistance with confocal microscopy and to A. Groyer for the IGFBP-3 cDNA.

This work has been supported by grants from the Fonds zur Förderung der Wissenschaftlichen Forschung (FWF) and the European Union (Biomed 2 program) to P.J.-D.