title: E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase (akt/PI3K) signaling pathway.
abstract: Intra-type genome variations of high risk Human papillomavirus (HPV) have been associated with a differential threat for cervical cancer development. In this work, the effect of HPV18 E6 isolates in Akt/PKB and Mitogen-associated protein kinase (MAPKs) signaling pathways and its implication in cell proliferation were analyzed. E6 from HPV types 16 and 18 are able to bind and promote degradation of Human disc large (hDlg). Our results show that E6 variants differentially modulate hDlg degradation, rebounding in levels of activated PTEN and PKB. HPV18 E6 variants are also able to upregulate phospho-PI3K protein, strongly correlating with activated MAPKs and cell proliferation. Data was supported by the effect of E6 silencing in HPV18-containing HeLa cells, as well as hDlg silencing in the tested cells. Results suggest that HPV18 intra-type variations may derive in differential abilities to activate cell-signaling pathways such as Akt/PKB and MAPKs, directly involved in cell survival and proliferation.
authors.affiliation: Unit of Biomedical Research in Cancer, National Cancer Institute (INCan)/Biomedical Research Institute (IIBM), National Autonomous University of Mexico (UNAM), Tlalpan, 14080 Mexico City, Mexico. adrycont@yahoo.com.mx
authors.forename: Adriana
authors.initials: A
authors.lastname: Contreras-Paredes
authors.forename: Erick
authors.initials: E
authors.lastname: De la Cruz-Hernández
authors.forename: Imelda
authors.initials: I
authors.lastname: Martínez-Ramírez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Dueñas-González
authors.forename: Marcela
authors.initials: M
authors.lastname: Lizano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000074288:Discs Large Homolog 1 Protein; D020868:Gene Silencing; D014644:Genetic Variation; D052161:Human papillomavirus 18 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C513314:DLG1 protein, human; C052603:E6 protein, Human papillomavirus type 18