title: The human papillomavirus type 18 E2 protein is a cell cycle-dependent target of the SCFSkp2 ubiquitin ligase.
abstract: The human papillomavirus type 18 (HPV-18) E2 gene is inactivated in cervical carcinoma after integration of the viral DNA into the host cellular genome. Since E2 represses the transcription of the two viral oncogenes E6 and E7, integration which allows their strong expression is considered a major step in transformation by HPV. We show here that E2 is specifically degraded at the end of the G(1) phase in a Brd4-independent manner, implying that its regulatory functions are cell cycle dependent. Degradation of E2 occurs via the Skp1/Cullin1/F-box Skp2 (SCF(Skp2)) ubiquitin ligase, since silencing of Skp2 induces stabilization of E2. In addition, the amino-terminal domain of E2 can interact with Skp2 as shown by coimmunoprecipitation experiments. We previously showed that E2 inhibits the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, leading to accumulation of several of its substrates. We demonstrate here that Skp2, which is a known APC/C substrate in G(1), is also stabilized by E2. Therefore, by negative feedback, SCF(Skp2) activation could lead to E2 degradation and E6/E7 expression specifically in the late G(1) phase. Moreover, since the SCF(Skp2) can trigger S-phase entry and Skp2 itself is a known oncogene, we believe that E2-mediated accumulation of Skp2, together with E2 degradation leading to putative release of E6 and E7 inhibition, could induce premature S-phase entry in HPV-infected cells, pointing to a direct role of E2 in the early steps of HPV-mediated transformation.
authors.affiliation: Papillomavirus Regulation and Cancer, Institute of Medical Biology, A*Star, Biopolis, Immunos, Singapore 138648. sophie.bellanger@imb.a-star.edu.sg
authors.forename: Sophie
authors.initials: S
authors.lastname: Bellanger
authors.forename: Chye Ling
authors.initials: CL
authors.lastname: Tan
authors.forename: Wenlong
authors.initials: W
authors.lastname: Nei
authors.forename: Ping Ping
authors.initials: PP
authors.lastname: He
authors.forename: Françoise
authors.initials: F
authors.lastname: Thierry
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000235:genetics; D016193:G1 Phase; D015967:Gene Expression Regulation, Viral; D052161:Human papillomavirus 18 / Q000502:physiology*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D044786:S-Phase Kinase-Associated Proteins; C069102:oncogene protein E2, Human papillomavirus type 18; D044767:Ubiquitin-Protein Ligases