title: Beta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 association.
abstract: The E6 oncoprotein from high-risk genus alpha human papillomaviruses (α-HPVs), such as HPV 16, has been well characterized with respect to the host-cell proteins it interacts with and corresponding signaling pathways that are disrupted due to these interactions. Less is known regarding the interacting partners of E6 from the genus beta papillomaviruses (β-HPVs); however, it is generally thought that β-HPV E6 proteins do not interact with many of the proteins known to bind to α-HPV E6. Here we identify p300 as a protein that interacts directly with E6 from both α- and β-HPV types. Importantly, this association appears much stronger with β-HPV types 5 and 8-E6 than with α-HPV type 16-E6 or β-HPV type 38-E6. We demonstrate that the enhanced association between 5/8-E6 and p300 leads to p300 degradation in a proteasomal-dependent but E6AP-independent manner. Rather, 5/8-E6 inhibit the association of AKT with p300, an event necessary to ensure p300 stability within the cell. Finally, we demonstrate that the decreased p300 protein levels concomitantly affect downstream signaling events, such as the expression of differentiation markers K1, K10 and Involucrin. Together, these results demonstrate a unique way in which β-HPV E6 proteins are able to affect host-cell signaling in a manner distinct from that of the α-HPVs.
authors: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Heather L
authors: HL
authors: Howie
authors: Jennifer I
authors: JI
authors: Koop
authors: Joleen
authors: J
authors: Weese
authors: Kristin
authors: K
authors: Robinson
authors: Greg
authors: G
authors: Wipf
authors: Leslie
authors: L
authors: Kim
authors: Denise A
authors: DA
authors: Galloway
mesh_terms: D002454:Cell Differentiation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D005819:Genetic Markers; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C466081:E6 protein, Human papillomavirus type 8; C487708:E6 protein, human papillomavirus type 5; D005819:Genetic Markers; D009856:Oncogene Proteins, Viral; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex