title: HPV16 E6 and E6AP differentially cooperate to stimulate or augment Wnt signaling.
abstract: The present study investigated the roles of E6 and E6AP in the Wnt pathway. We showed that E6 levels are markedly reduced in cells in which Wnt signaling is activated. Coexpression of wild-type or mutant E6AP (C820A) in Wnt-activated cells stabilized E6 and enhanced Wnt/β-catenin/TCF transcription. Expression of E6AP alone in nonstimulated cells elevated β-catenin level, promoted its nuclear accumulation, and activated β-catenin/TCF transcription. A knockdown of E6AP lowered β-catenin levels. Coexpression with E6 intensified the activities of E6AP. Further experiments proved that E6AP/E6 stabilize β-catenin by protecting it from proteasomal degradation. This function was dependent on the catalytic activity of E6AP, the kinase activity of GSK3β and the susceptibility of β-catenin to GSK3β phosphorylation. Thus, this study identified E6AP as a novel regulator of the Wnt signaling pathway, capable of cooperating with E6 in stimulating or augmenting Wnt/β-catenin signaling, thereby possibly contributing to HPV carcinogenesis.
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: sophia.tab@gmail.com.
authors.forename: Sophia
authors.initials: S
authors.lastname: Sominsky
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: ykuslansky@gmail.com.
authors.forename: Yael
authors.initials: Y
authors.lastname: Kuslansky
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: benyshap@gmail.com.
authors.forename: Beny
authors.initials: B
authors.lastname: Shapiro
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: jackman@post.tau.ac.il.
authors.forename: Anna
authors.initials: A
authors.lastname: Jackman
authors.affiliation: Research Division, The Peter MacCallum Cancer Centre, East Melbourne, Australia. Electronic address: ygal.haupt@petermac.org.
authors.forename: Ygal
authors.initials: Y
authors.lastname: Haupt
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: arina@post.tau.ac.il.
authors.forename: Rina
authors.initials: R
authors.lastname: Rosin-Arbesfeld
authors.affiliation: Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: lsherman@post.tau.ac.il.
authors.forename: Levana
authors.initials: L
authors.lastname: Sherman
mesh_terms: D002478:Cells, Cultured; D003001:Cloning, Molecular; D005786:Gene Expression Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015603:Keratinocytes; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010957:Plasmids; D046988:Proteasome Endopeptidase Complex; D055550:Protein Stability; D012097:Repressor Proteins / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: E6AP; GSK3β; HPV E6; HPV E7; Wnt signaling; β-catenin