Carcinogenesis Advance Access published online on September 7, 2007
Carcinogenesis, doi:10.1093/carcin/bgm199
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human papillomavirus type 16 E7 oncoprotein inhibits apoptosis mediated by nuclear insulin-like growth factor binding protein-3 by inducing its ubiquitin/proteasome-dependent degradation
1 Cell Metabolism and Differentiation Research Group
2 Department for Molecular and Cellular Biology, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, Rennweg 10, 6020 Innsbruck, Austria
3 Tumorvirology Group
4 Molecular Oncology Group, Tyrolean Cancer Research Institute, Medical University Innsbruck, Innrain 66, 6020 Innsbruck, Austria
* Corresponding author: Werner Zwerschke, Institute for Biomedical Aging Research and Tyrolean Cancer Research Institute, Rennweg 10, 6020 Innsbruck, Austria, Tel.: 0043-512-58391932, Fax: 0043-512-5839198, E-mail: 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 COOH-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.
Received March 7, 2007; revised August 27, 2007; accepted August 28, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. J. Cobb, H. Mehta, and P. Cohen Enhancing the Apoptotic Potential of Insulin-Like Growth Factor-Binding Protein-3 in Prostate Cancer by Modulation of CK2 Phosphorylation Mol. Endocrinol., October 1, 2009; 23(10): 1624 - 1633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Yamada and K.-W. Lee Perspectives in mammalian IGFBP-3 biology: local vs. systemic action Am J Physiol Cell Physiol, May 1, 2009; 296(5): C954 - C976. [Abstract] [Full Text] [PDF]
|
|