title: The HPV16 E6 oncoprotein and UVB irradiation inhibit the tumor suppressor TGFβ pathway in the epidermis of the K14E6 transgenic mouse.
abstract: High-risk human papillomaviruses (HR-HPVs) are the causative agents of cervical cancer, and they are also associated with a subset of head and neck squamous cell carcinomas. In addition, HPVs have also been postulated in the development of non-melanoma skin cancers (NMSC). In these cancers, the oncogene E6 is best known for its ability to inactivate the tumor suppressor p53 protein. Interestingly, in transgenic mice for HPV16 E6 (K14E6), it was reported that E6 alone induced epithelial hyperplasia and delay in differentiation in skin epidermis independently of p53 inactivation. Transforming growth factor β (TGFβ) is an important regulator of cell growth/differentiation and apoptosis, and this pathway is often lost during tumorigenesis. Ultraviolet radiation B (UVB) exposure activates diverse cellular responses, including DNA damage and apoptosis. In this study, we investigated whether the E6 oncogene alone or in combination with UVB dysregulate some components of the TGFβ pathway in the epidermis of K14E6 mice. We used 8-day-old K14E6 and non-transgenic mice irradiated and unirradiated with a single dose of UVB. We found that the E6 oncogene and UVB irradiation impair the TGFβ pathway in epidermis of K14E6 mice by downregulation of the TGFβ type II receptor (TβRII). This loss of TβRII prevents downstream activation of Smad2 and target genes as p15, an important regulator of cell cycle progression. In summary, the TGFβ signalling in cells of the epidermis is downregulated in our mouse model by both the E6 oncoprotein and the UVB irradiation.
authors.affiliation: Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Marco
authors.initials: M
authors.lastname: Popoca-Cuaya
authors.affiliation: Unit of Biomedical Research in Cancer, UNAM/Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.
authors.forename: Jose
authors.initials: J
authors.lastname: Diaz-Chavez
authors.affiliation: Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Jesus
authors.initials: J
authors.lastname: Hernandez-Monge
authors.affiliation: Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Alvarez-Rios
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico City, Mexico.
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation / Q000235:genetics / Q000528:radiation effects; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000528:radiation effects*; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53
keywords: E6 oncoprotein; HPV16; transforming growth factor β; transgenic mice; ultraviolet radiation B