The human papillomavirus type 16 E5 oncoprotein synergizes with EGF-receptor signaling to enhance cell cycle progression and the down-regulation of p27(Kip1).
E5 oncoprotein activity from high risk human papillomaviruses (HPVs) is associated with growth factor receptor signaling, but the function of this protein is not well understood. In this study, we investigated the role of HPV-16 E5 on the cell cycle progression during EGF-stimulation. Wild-type and NIH 3T3 cells over-expressing human EGF-receptor were transfected with HPV-16 E5 gene and the cell cycle progression was characterized. This analysis showed that the E5-expressing cells increased DNA synthesis (S-phase) by around 40%. Cell cycle protein analysis of E5-expressing cells showed a reduction in the half-life of p27(Kip1) protein as compared to control cells (18.4 vs. 12.7 h), an effect that was enhanced in EGF-stimulated cells (12.8 vs. 3.6 h). Blockage of EGF-receptor activity abrogated E5 signals as well as p27(Kip1) down-regulation. These results suggest that E5 and the EGF-receptor cooperate to enhance cell cycle entry and progression through regulating p27(Kip1) expression at protein level.
Pedroza-Saavedra
Adolfo
A
Center for Research on Infectious Diseases, National Institute of Public Health, Cuernavaca, Morelos 62100, Mexico.
Lam
Eric W-F
EW
Esquivel-Guadarrama
Fernando
F
Gutierrez-Xicotencatl
Lourdes
L
D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005814:Genes, Viral; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000086082:Viroporin Proteins
D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; C493961:Cdkn1b protein, mouse; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins