The E5 oncoprotein of human papillomavirus type 16 enhances endothelin-1-induced keratinocyte growth.
Human keratinocytes express ETA receptors and produce endothelin-1 (ET-1), which stimulates growth response. Previously, we reported that a twofold increase in ETA receptors is present in human papillomavirus type 16 (HPV16) immortalized keratinocytes and that ET-1 induces enhanced proliferative response in these cell lines compared to normal cells. The present studies examine whether the E5 gene of HPV16 is responsible for the enhanced activity of ET-1 in HPV-transfected keratinocytes. The presence of the E5 gene in growth factor-starved keratinocytes induced the DNA synthesis and enhanced the mitogenic activity of ET-1 or epidermal growth factor. The selection of primary keratinocytes in growth factor-free medium with the addition of ET-1 as a growth factor showed that E5-transfected keratinocytes were able to grow and to form a higher number of larger colonies with respect to untransfected cells. This effect seems to be related to the interaction of E5 with the mitogenic signaling pathway of ET-1 rather than to an increase in the expression of the receptors for ET-1. In conclusion, our data demonstrate that E5 enhances ligand signaling in keratinocytes outside the EGF pathway by the amplification of the proliferative effect of ET-1/ETA receptor signaling.
Laboratory of Virology, Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Institute for Cancer Research, CRS, via delle Messi d'Oro 156, Rome, 00158, Italy. venuti@crs.ifo.it
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Venuti
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Salani
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Poggiali
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Manni
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Bagnato
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000821:virology*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000502:physiology*; D027383:Papillomaviridae / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D000086082:Viroporin Proteins
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004815:Epidermal Growth Factor; D009856:Oncogene Proteins, Viral; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D011994:Recombinant Proteins; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins; C072247:cyclo(Trp-Asp-Pro-Val-Leu)