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Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells

Oncogene volume 20, pages 4740–4749 (2001)Cite this article

Abstract

High-risk human papillomaviruses (HPVs) are etiologically linked to human cervical and oral cancers. The E6 and E7 oncoproteins encoded by HPV target host cell tumor suppressor proteins. E6 induces proteolysis of p53 through the ubiquitin-proteasome pathway. Recent studies showed that overexpression of E7 caused proteolytic degradation of the tumor suppressor Rb. However, unlike p53, Rb is not regulated by proteolysis in normal cells. In addition, it was unclear whether in its natural context E7 regulates Rb through the ubiquitin-proteasome pathway. Therefore, we sought to determine whether Rb is regulated by the ubiquitin-proteasome pathway in HPV-containing tumor cells. We carried out a detailed analysis in Caski cells, that are derived from HPV-containing cervical cancer tissues. Studies with various protease inhibitors revealed that Rb is regulated specifically by the ubiquitin-proteasome pathway in HPV-containing cervical tumor cells. Several inhibitors of the 26S proteasome significantly increased the level of Rb in the Caski cells. Rb controls cell growth by forming complexes with the E2F-family transcription factors. Surprisingly, in spite of a significant accumulation of the hypophosphorylated form of Rb, no Rb/E2F complex was detectable in the proteasome inhibitor treated cells. Further analysis revealed that there was an increased accumulation of the E7 oncoprotein. We showed that the proteasome inhibitors simultaneously blocked the proteolysis of E7 and Rb, suggesting that E7 is also regulated by the ubiquitin-dependent proteolysis in cervical cancer cells. Taken together, this study suggests that targeted inhibition of Rb proteolysis will be required for restoring Rb function in HPV-containing cervical cancer cells.

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Acknowledgements

We are grateful to Dirk Bohman of Heidelberg, Germany for generously providing the His6-tagged ubiquitin expression plasmid. We thank Ms Diane Rudall for editorial assistance in preparing this manuscript. Support for this research was provided by the grants DE12506 from the National Institute of Dental Research and CA76276 from the National Cancer Institute.

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Authors and Affiliations

  1. Center for Molecular Biology of Oral Diseases, College of Dentistry (M/C 860), University of Illinois at Chicago, 801 South Paulina Street, Chicago, IL-60612, Illinois, USA

    Jing Wang, Aruna Sampath & Srilata Bagchi

  2. Biochemistry and Molecular Biology, University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL-60612, Illinois, USA

    Pradip Raychaudhuri

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  1. Jing Wang
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  2. Aruna Sampath
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Correspondence to Srilata Bagchi.

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Wang, J., Sampath, A., Raychaudhuri, P. et al. Both Rb and E7 are regulated by the ubiquitin proteasome pathway in HPV-containing cervical tumor cells. Oncogene 20, 4740–4749 (2001). https://doi.org/10.1038/sj.onc.1204655

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