title: Cellular steady-state levels of "high risk" but not "low risk" human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53- and E6AP-binding capabilities.
abstract: The group of mucosal epithelia-infecting human papillomaviruses (HPV) can be subdivided in "low" and "high risk" HPV types. Both types induce benign neoplasia (condyloma), but only the infection with a "high risk" HPV type is causally associated with an increased risk of developing anogenital tumors. The oncogenic potential of high risk HPVs resides at least partially in the viral E6 protein. The E6 protein targets the cellular p53 protein for proteasome-dependent degradation, which is associated with the immortalizing and transforming functions of these viruses. Recently the E6-dependent proteasome-mediated destabilization of additional cellular proteins (E6TP1, c-myc, Bak, hMCM7, human scribble, E6AP, MAGI-1) has been described, but the cellular mechanisms controlling the viral E6 protein stability itself have been so far not analyzed. In this study, we transiently expressed the E6 genes of the high risk HPV type 16, the low risk HPV types 6a and 11, and the cutaneous epithelia-infecting HPV types 5 and 8 from a eucaryotic expression vector and compared the cellular steady-state levels of the expressed E6 proteins. We demonstrated that the high risk HPV 16 E6 protein possesses the lowest steady-state level in comparison to the low risk HPV type E6 proteins and the cutaneous epithelia-infecting HPV type E6 proteins. Inhibition of cellular proteasome-dependent protein degradation led to an increase in steady-state levels of high risk but not of low risk E6 proteins. Analysis of functionally deficient HPV 16 E6 proteins in p53 null- and p53 wild-type-expressing cell lines revealed that the cellular steady-state level of this protein is influenced neither by its p53- nor its E6AP-binding abilities.
authors.affiliation: Department of Pharmacology and Toxicology, Philipps University Marburg, Karl-von-Frisch Strasse 1, D-35033, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Kehmeier
authors.forename: Heiko
authors.initials: H
authors.lastname: Rühl
authors.forename: Britta
authors.initials: B
authors.lastname: Voland
authors.forename: Melissa Conrad
authors.initials: MC
authors.lastname: Stöppler
authors.forename: Elliot
authors.initials: E
authors.lastname: Androphy
authors.forename: Hubert
authors.initials: H
authors.lastname: Stöppler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases; D017353:Gene Deletion; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008025:Ligases / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009856:Oncogene Proteins, Viral / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000821:virology; D046988:Proteasome Endopeptidase Complex; D012097:Repressor Proteins; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000821:virology; D044767:Ubiquitin-Protein Ligases
chemical_list: D000970:Antineoplastic Agents; C068651:E6 protein, Human papillomavirus type 16; D007976:Leupeptins; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde