title: The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin.
abstract: The oncoprotein E7 from human papillomavirus-16 (HPV-16 E7) plays a pivotal role in HPV postinfective carcinogenesis, and its physical interaction with host cell targets is essential to its activity. We identified a novel cellular partner for the viral oncoprotein: the actin-binding protein gelsolin (GSN), a key regulator of actin filament assembly and disassembly. In fact, biochemical analyses, generation of a 3D molecular interaction model and the use of specific HPV-16 E7 mutants provided clear cut evidence supporting the crucial role of HPV-16 E7 in affecting GSN integrity and function in human immortalized keratinocytes. Accordingly, functional analyses clearly suggested that stable HPV-16 E7 expression induced an imbalance between polymeric and monomeric actin in favor of the former. These events also lead to changes of cell cycle (increased S phase), to the inhibition of apoptosis and to the increase of cell survival. These results provide support to the hypotheses generated from the 3D molecular interaction model and encourage the design of small molecules hindering HPV-induced host cell reprogramming by specifically targeting HPV-16 E7-expressing cells.
authors.affiliation: Department of Development of Therapeutic Programs, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Mileo
authors.forename: Claudia
authors.initials: C
authors.lastname: Abbruzzese
authors.forename: Carmen
authors.initials: C
authors.lastname: Vico
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Barbara
authors.initials: B
authors.lastname: Ascione
authors.forename: Antonio
authors.initials: A
authors.lastname: Federico
authors.forename: Stefano
authors.initials: S
authors.lastname: Della Bianca
authors.forename: Stefano
authors.initials: S
authors.lastname: Mattarocci
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.forename: Marco G
authors.initials: MG
authors.lastname: Paggi
mesh_terms: D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D018260:Gelsolin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D009154:Mutation; D050725:Papillomavirus E7 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping
chemical_list: D000199:Actins; D018260:Gelsolin; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D053148:Caspase 3