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Molecular and Cellular Biology, September 2000, p. 6483-6495, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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

Boris Mannhardt,1,2,3 Stuart A. Weinzimer,4 Mechthild Wagner,2 Marc Fiedler,2,3 Pinchas Cohen,4,dagger Pidder Jansen-Dürr,2,3 and Werner Zwerschke1,2,3,*

Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, INF 242, D-69120 Heidelberg, Germany1; Institut für Biomedizinische Alternsforschung der Österreichischen Akademie der Wissenschaften2 and Tiroler Krebsforschungsinstitut,3 6020 Innsbruck, Austria; and Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 191044

Received 28 December 1999/Returned for modification 11 February 2000/Accepted 12 June 2000

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.

* Corresponding author. Mailing address: Tiroler Krebsforschungsinstitut, Innrain 66, 6020 Innsbruck, Austria. Phone: 43-512-570485-45. Fax: 43-512-570485-44. E-mail: werner.zwerschke{at}uklibk.ac.at.

dagger Present address: Department of Pediatrics, Division of Endocrinology, Mattell Children's Hospital at UCLA, Los Angeles, CA 90095-1752.

Molecular and Cellular Biology, September 2000, p. 6483-6495, Vol. 20, No. 17
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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