title: The E6 oncoprotein from HPV16 enhances the canonical Wnt/β-catenin pathway in skin epidermis in vivo.
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.
authors.affiliation: Deptamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados (Cinvestav), México, México.
authors.forename: José
authors.initials: J
authors.lastname: Bonilla-Delgado
authors.forename: Gülay
authors.initials: G
authors.lastname: Bulut
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Liu
authors.forename: Enoc M
authors.initials: EM
authors.lastname: Cortés-Malagón
authors.forename: Richard
authors.initials: R
authors.lastname: Schlegel
authors.forename: Catalina
authors.initials: C
authors.lastname: Flores-Maldonado
authors.forename: Rubén G
authors.initials: RG
authors.lastname: Contreras
authors.forename: Sang-Hyuk
authors.initials: SH
authors.lastname: Chung
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.forename: Aykut
authors.initials: A
authors.lastname: Uren
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002522:Chlorocebus aethiops; D004817:Epidermis / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007763:Lac Operon / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D054731:PDZ Domains / Q000235:genetics; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000821:virology; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D051176:beta Catenin