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Int. J. Mol. Sci. 2018, 19(10), 3153; https://doi.org/10.3390/ijms19103153

HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor

1
Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City 14080, Mexico
2
Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
3
CONACyT-Instituto Nacional de Cancerología, Mexico City 14080, Mexico
4
Departamento de Farmacobiología, Centro de Investigación y Estudios Avanzados del Instituto Politécnico Nacional, Sede sur, Mexico City 14330, Mexico
5
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico
*
Author to whom correspondence should be addressed.
Received: 6 August 2018 / Revised: 29 September 2018 / Accepted: 9 October 2018 / Published: 13 October 2018
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)
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Abstract

The Wnt/β-catenin signaling pathway regulates cell proliferation and differentiation and its aberrant activation in cervical cancer has been described. Persistent infection with high risk human papillomavirus (HR-HPV) is the most important factor for the development of this neoplasia, since E6 and E7 viral oncoproteins alter cellular processes, promoting cervical cancer development. A role of HPV-16 E6 in Wnt/β-catenin signaling has been proposed, although the participation of HPV-18 E6 has not been previously studied. The aim of this work was to investigate the participation of HPV-18 E6 and E6*I, in the regulation of the Wnt/β-catenin signaling pathway. Here, we show that E6 proteins up-regulate TCF-4 transcriptional activity and promote overexpression of Wnt target genes. In addition, it was demonstrated that E6 and E6*I bind to the TCF-4 (T cell factor 4) and β-catenin, impacting TCF-4 stabilization. We found that both E6 and E6*I proteins interact with the promoter of Sp5, in vitro and in vivo. Moreover, although differences in TCF-4 transcriptional activation were found among E6 intratype variants, no changes were observed in the levels of regulated genes. Furthermore, our data support that E6 proteins cooperate with β-catenin to promote cell proliferation. View Full-Text
Keywords: HPV-18 E6; HPV-18 E6*I; TCF-4 transcription factor; Wnt/β-catenin signaling HPV-18 E6; HPV-18 E6*I; TCF-4 transcription factor; Wnt/β-catenin signaling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Muñoz-Bello, J.O.; Olmedo-Nieva, L.; Castro-Muñoz, L.J.; Manzo-Merino, J.; Contreras-Paredes, A.; González-Espinosa, C.; López-Saavedra, A.; Lizano, M. HPV-18 E6 Oncoprotein and Its Spliced Isoform E6*I Regulate the Wnt/β-Catenin Cell Signaling Pathway through the TCF-4 Transcriptional Factor. Int. J. Mol. Sci. 2018, 19, 3153.

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