The E7 protein from human papillomavirus type 16 enhances keratinocyte migration in an Akt-dependent manner.
Cyclin-dependent kinase inhibitor p27(kip1) (p27) has recently been implicated as a positive regulator of cellular motility and is a marker of poor prognosis in several forms of cancer when localized to the cytoplasm. Cytoplasmic p27 exerts its effect on migration by binding to and inhibiting the activation of the small GTPase and cytoskeletal organizer RhoA, consequentially loosening cell substrate grip and enhancing movement. Using DNA damage as a p27 nuclear import signal, we found that the E7 oncoprotein from human papillomavirus type 16 (HPV-16), the etiological agent of cervical cancer, enhanced both the cytoplasmic retention of p27 and the migration of human foreskin keratinocytes (HFKs) in a phosphoinositide-3 kinase (PI3K)/Akt-dependent manner using a standard wound assay. Increased migration in E7-expressing HFKs correlated with an Akt-regulated downregulation of RhoA activity through p27 binding under conditions where a p27 nuclear import signal is given (that is, DNA damage). Under these conditions, inhibition of the downstream RhoA effector ROCK enhanced control cell migration, whereas relatively unaffecting E7-expressing cells, further implicating that the inhibitory effect of E7 on RhoA positively regulates migration. We believe that the E7 protein from HPV-16 can modulate the cytoplasmic localization of p27 and may in turn regulate tumor metastasis/aggressiveness through the PI3K/Akt pathway.
Charette
S T
ST
Department of Microbiology and Immunology, University of Rochester, Rochester, NY, USA.
McCance
D J
DJ
D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D052816:Foreskin / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein