title: Regulation of p14ARF expression by HPV-18 E6 variants.
abstract: A common causative agent for uterine cervical cancer is the human papillomavirus type 18 (HPV-18) which has three phylogenic variants: Asian-Amerindian, European, and African. Each variant shows significant molecular differences in the E6 gene. E6 oncoprotein is a negative regulator of tumor suppressor protein p53, hence, this oncoprotein indirectly regulates the expression of tumor-suppressor p14(ARF) . p14(ARF) and p16(INK4A) genes are overexpressed in--and have been proposed as markers for--HPV-related cervical cancer. In order to dissect the role of E6 on the regulation of p14(ARF) expression, separating it from that of other intervening factors, transfection of E6 variants to MCF-7 cells was performed, assessing cDNA transcript levels by RT-PCR, whereas p14(ARF) and p53 expression were evaluated by immunocytochemistry and Western blot. E6 transfected cells differentially expressed transcripts of two molecular forms: E6 and E6*. The ratio of these two forms varied with the transfected E6 variant. With the Asian-Amerindian variant, the ratio was E6 > E6*, whereas with the European and the African the ratio was E6* > E6. As expected with the E6* construct, E6* transcripts were solely observed. In addition, when E6 > E6* and p53 expression was low, p14(ARF) was high and when E6* > E6 and p53 expression was high, p14(ARF) was low. In conclusion, each E6 variant distinctively affects p53 levels and consequently p14(ARF) expression, finding that could be related with the differences in oncogenic effect of infection with the diverse high-risk HPV variants.
authors.affiliation: Department of Pathology, Hospital of Gynecology and Pediatrics 3A, Instituto Mexicano del Seguro Social, Delegación Norte, Mexico, DF, Mexico.
authors.forename: Salvador
authors.initials: S
authors.lastname: Vazquez-Vega
authors.forename: Lilia Patricia
authors.initials: LP
authors.lastname: Sanchez-Suarez
authors.forename: Rafael
authors.initials: R
authors.lastname: Andrade-Cruz
authors.forename: Emilio
authors.initials: E
authors.lastname: Castellanos-Juarez
authors.forename: Adriana
authors.initials: A
authors.lastname: Contreras-Paredes
authors.forename: Marcela
authors.initials: M
authors.lastname: Lizano-Soberon
authors.forename: Alejandro
authors.initials: A
authors.lastname: Garcia-Carranca
authors.forename: Luis
authors.initials: L
authors.lastname: Benitez Bribiesca
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D052161:Human papillomavirus 18 / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53
keywords: E6 variants; HPV-18; p14ARF; p16INK4A; transfection