Carcinogenesis Advance Access originally published online on September 7, 2007
Carcinogenesis 2007 28(12):2511-2520; doi:10.1093/carcin/bgm199
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Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor-binding protein-3 by enhancing its ubiquitin/proteasome-dependent degradation
1 Cell Metabolism and Differentiation Research Group, Rennweg 10, 6020 Innsbruck, Austria
2 Tumorvirology Group, Medical University Innsbruck, Innrain 66, 6020 Innsbruck, Austria
3 Department for Molecular and Cellular Biology Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria
4 Molecular Oncology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innrain 66, 6020 Innsbruck, Austria
* To whom correspondence should be addressed. Tel: +43 512 58391932; Fax: +43 512 5839198; Email: werner.zwerschke{at}oeaw.ac.at
The E7 protein encoded by the oncogenic human papillomavirus type 16 has been shown to bind and inactivate insulin-like growth factor-binding protein-3 (IGFBP-3), the pro-apoptotic product of a tumour suppressor gene; however, the molecular mechanism underlying E7-induced inactivation of IGFBP-3 remained uncertain. In this study, we map the IGFBP-3-binding domain for E7 to the nuclear localization signal in the conserved C-terminal domain of IGFBP-3. Moreover, we demonstrate that both proteins interact in the nucleus and that E7 induces polyubiquitination and proteasome-dependent proteolysis of nuclear IGFBP-3 in cervical cancer cells. This leads to a dramatic shortening of the half-life of nuclear IGFBP-3, whereas the stability of an E7-non-binding IGFBP-3 mutant is not affected by E7. Finally, we show that E7-mediated destruction of nuclear IGFBP-3 correlates with the inhibition of IGFBP-3-induced apoptotic cell death. These data are consistent with E7-induced ubiquitin/proteasome-dependent inactivation of nuclear IGFBP-3.
Abbreviations: GST, glutathione S-transferase; HPV, human papillomavirus; IGF-I, insulin-like growth factor-I; IGFBP-3, insulin-like growth factor-binding protein-3; IGF-R, IGF-receptor; NLS, nuclear localization sequence; PBS, phosphate-buffered saline; pRb, retinoblastoma protein; SDS–PAGE, sodium dodecyl sulphate–polyacrylamide gel electrophoresis
Received March 7, 2007; revised August 27, 2007; accepted August 28, 2007.
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