Human papillomavirus 16
2006 Jun 1;66(11):5555-9. Virus
Genes. 2006 Jun;32(3):327-34.
Human papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma protein.
Menges CW, Baglia LA, Lapoint R, McCance DJ.
Department of Biochemistry and Biophysics,
Human papillomaviruses (HPV) are small DNA tumor viruses causally associated with cervical cancer. The early gene product E7 from high-risk HPV is considered the major transforming protein expressed by the virus. Although many functions have been described for E7 in disrupting normal cellular processes, we describe in this study a new cellular target in primary human foreskin keratinocytes (HFK), the serine/threonine kinase AKT. Expression of HPV type 16 E7 in HFK caused inhibition of differentiation, hyperproliferation, and up-regulation of AKT activity in organotypic raft cultures. The ability of E7 to up-regulate AKT activity is dependent on its ability to bind to and inactivate the retinoblastoma (Rb) gene product family of proteins. Furthermore, we show that knocking down Rb alone, with short hairpin RNAs, was sufficient to up-regulate AKT activity in differentiated keratinocytes. Up-regulation of AKT activity and loss of Rb was also observed in HPV-positive cervical high-grade squamous intraepithelial lesions when compared with normal cervical tissue. Together, these data provide evidence linking inactivation of Rb by E7 in the up-regulation of AKT activity during cervical cancer progression.
PMID: 16740689 [PubMed - in process]
Functional Role of Phosphatidylinositol 3-kinase/Akt Pathway on Cell Growth and Lytic Cycle of Epstein-Barr Virus in the Burkitt's Lymphoma Cell Line, P3HR-1.
Mori T, Sairenji T.
Division of Biosignaling, Department of Biomedical Sciences,
The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is involved in various malignancies, but the role of PI3-K/Akt pathway in Epstein-Barr virus (EBV) infected Burkitt's lymphoma (BL) cells remains unclear. To elucidate therapeutic targets for BL, this study investigates the effect of PI3-K/Akt pathway in: EBV-positive BL cell lines Raji, P3HR-1, Akata and Daudi; and EBV-negative BL cell lines Ramos and BJAB. Results of analyses indicate that Akt was constitutively phosphorylated in BJAB, P3HR-1, Akata, and Daudi but not in Ramos and Raji cells. We characterized Akt phosphorylation on cell growth and EBV lytic cycle in P3HR-1 cells, which were phosphorylated most intensively. The Akt was equally phosphorylated in cells cultured with and without fetal bovine serum for a few days. Akt phosphorylation and cell growth were inhibited by PI3-K specific inhibitor LY294002 in a dose-dependent manner. LY294002 markedly down regulated expression of EBV lytic gene BRLF1 protein Rta, BMRF1 protein EA-D, but not BZLF1 protein ZEBRA. The inhibitor reduced viral capsid antigen (VCA) positive cells. Down regulation of Rta by LY294002 occurred at the transcriptional level. These results demonstrate that PI3-K/Akt pathway is activated constitutively in P3HR-1 cells; it promotes cell growth and the lytic cycle cascade downstream of ZEBRA.
PMID: 16732486 [PubMed - in process]
Cancer Res. 2006 Jun 1;66(11):5555-9.
Virus Genes. 2006 Jun;32(3):327-34.