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The E6 Oncoprotein from HPV16 Enhances the Canonical Wnt/β-Catenin Pathway in Skin Epidermis In Vivo

Bonilla-Delgado, José, Bulut, Gülay, Liu, Xuefeng, Cortés-Malagón, Enoc M., Schlegel, Richard, Flores-Maldonado, Catalina, Contreras, Rubén G., Chung, Sang-Hyuk, Lambert, Paul F., Üren, Aykut, Gariglio, Patricio·2012·Molecular Cancer Research
DOI 10.1158/1541-7786.mcr-11-0287PMC PMC3332097

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Abstract

The contribution of the Wnt signaling pathway to human papilloma virus (HPV)-induced carcinogenesis is poorly understood. In high-grade dysplastic lesions that are caused by high-risk HPVs (HR-HPV), β-catenin is often located in the cell nucleus, which suggests that Wnt pathway may be involved in the development of HPV-related carcinomas. Most of the oncogenic potential of HR-HPVs resides on the PDZ-binding domain of E6 protein. We hypothesized that the PDZ-binding domain of the HPV16-E6 oncoprotein induces the nuclear accumulation of β-catenin due to its capacity to degrade PDZ-containing cellular targets. To test this hypothesis, we evaluated the staining pattern of β-catenin in the skin epidermis of transgenic mice expressing the full-length E6 oncoprotein (K14E6 mice) and measured LacZ gene expression in K14E6 mice that were crossed with a strain expressing LacZ that was knocked into the Axin2 locus (Axin2+/LacZ mice). Here, we show that the E6 oncoprotein enhances the nuclear accumulation of β-catenin, the accumulation of cellular β-catenin–responsive genes, and the expression of LacZ. None of these effects were observed when a truncated E6 oncoprotein that lacks the PDZ-binding domain was expressed alone (K14E6ΔPDZ mice) or in combination with Axin2+/LacZ. Conversely, cotransfection with either E6 or E6ΔPDZ similarly enhanced canonical Wnt signaling in short-term in vitro assays that used a luciferase Wnt/β-catenin/TCF-dependent promoter. We propose that the activation of canonical Wnt signaling could be induced by the HPV16-E6 oncoprotein; however, the participation of the E6 PDZ-binding domain seems to be important in in vivo models only. Mol Cancer Res; 10(2); 250–8. ©2011 AACR.

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Cited by

Metadata

Authors
Bonilla-Delgado, J., Bulut, G., Liu, X., Cortés-Malagón, E. M., Schlegel, R., Flores-Maldonado, C., Contreras, R. G., Chung, S.-H., Lambert, P. F., Üren, A., & Gariglio, P.
Affiliations
Authors' Affiliations: Departments of 1Genetics and Molecular Biology and 2Physiology Biophysics and Neurosciences, Centro de Investigación y de Estudios Avanzados (Cinvestav), Mexico City, Mexico; Departments of 3Oncology and 4Pathology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; 5University of Wisconsin, School of Medicine and Public Health, McArdle Laboratory for Cancer Research, Madison, Wisconsin; and 6Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas
Venue
Molecular Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2012-02-01
Volume
10
Issue
2
Pages
250-258
ISSN
  • 1541-7786
  • 1557-3125
DOI
10.1158/1541-7786.mcr-11-0287
PMC
PMC3332097
Cited by
50
References
1
Language
en

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