title: Human papillomavirus 16 E2 interacts with neuregulin receptor degradation protein 1 affecting ErbB-3 expression in vitro and in clinical samples of cervical lesions.
abstract: The ErbB tyrosine kinase receptors play a key role in regulating many cellular functions and human papillomaviruses (HPVs) may interact with transductional pathway of different growth factor receptors. Here, these interactions were analysed in W12 cell line carrying HPV 16 genome and in clinical samples. W12 cells, in which HPV16 becomes integrated during passages, were utilised to detect viral and ErbB family expression at early (W12E) and late passages (W12G). Interestingly, a strong reduction of ErbB-3 expression was observed in W12G. Loss of the E2 and E5 viral genes occurs in W12G and this may affect ErbB-3 receptor expression. E2 and E5 rescue experiments demonstrated that only E2 gene was able to restore ErbB-3 expression. E2 is a transcriptional factor but the expression levels of ErbB3 were unaffected and ErbB-3 promoter did not show any consensus sequence for E2, thus E2 may interact in another way with ErbB3. Indeed, HPV 16 E2 can modulate ErbB-3 by interacting with the ubiquitin ligase neuregulin receptor degradation protein 1 (Nrdp-1) that is involved in the regulation of this receptor, via ubiquitination and degradation. E2 co-immunoprecipitated in a complex with Nrdp-1 leading to hypothesise an involvement of this interaction in ErbB-3 regulation. In addition, 90% of the clinical samples with integrated virus and E2 loss showed no or low ErbB-3 positivity, confirming in vitro results. In conclusion, the new discovered interaction of HPV-16 E2 with Nrdp-1 may affect ErbB-3 expression.
authors.affiliation: Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Paolini
authors.affiliation: Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Gianfranca
authors.initials: G
authors.lastname: Curzio
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Melucci
authors.affiliation: Biostatistic Unit-Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Antoniani
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Carosi
authors.affiliation: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Vici
authors.affiliation: Department of Gynaecologic Oncology, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Laboratory of Virology, Regina Elena National Cancer Institute, Rome, Italy; HPV-Unit, Regina Elena National Cancer Institute, Rome, Italy. Electronic address: venuti@ifo.it.
authors.forename: Aldo
authors.initials: A
authors.lastname: Venuti
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology; D011485:Protein Binding; D059748:Proteolysis; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology; D016662:Virus Integration; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000821:virology
chemical_list: D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3
keywords: CIN; Cervical cancer; E2 protein; EGFR; ErbB-3; HPV; IHC; Nrdp-1; W12 cell line