This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, B. Articles by Roman, A. Search for Related Content PubMed PubMed Citation Articles by Zhang, B. Articles by Roman, A.

 Previous Article  |  Next Article 

Journal of Virology, January 2002, p. 220-231, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.220-231.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

E5 Protein of Human Papillomavirus Type 16 Protects Human Foreskin Keratinocytes from UV B-Irradiation-Induced Apoptosis

Department of Microbiology and Immunology,¹ Indiana University School of Medicine, and Walther Cancer Institute, Indianapolis, Indiana 46202-5120,² Departments of Dermatology and Biochemistry and Molecular Biology³

Received 27 June 2001/ Accepted 26 September 2001

The human papillomavirus type 16 (HPV16) E5 protein associates with the epidermal growth factor receptor (EGFR) and enhances the activation of the EGFR after stimulation by EGF in human keratinocytes. Phosphatidylinositol 3-kinase (PI3K) and ERK1/2 mitogen-activated protein kinase (ERK1/2 MAPK), two signal molecules downstream of the EGFR, have been recognized as participants in two survival signal pathways in response to stress. The fact that E5 can enhance EGFR activation suggests that E5 might act as a survival factor. To test this hypothesis, the apoptotic response of UV B-irradiated primary keratinocytes infected with either control retrovirus, LXSN, or HPV16 2E5-expressing recombinant retrovirus was quantitated. Under the same conditions, LXSN-infected cells showed extensive apoptosis, while E5-expressing cells demonstrated a significant reduction in UV B-irradiation-induced apoptosis. The E5-mediated protection against apoptosis was blocked by wortmannin and PD98059, specific inhibitors of the PI3K and ERK1/2 MAPK pathways, respectively, suggesting that the PI3K and ERK1/2 MAPK pathways are involved in this process. Western blot analysis showed that Akt (also named protein kinase B), which is a downstream effector of PI3K, and ERK1/2 MAPK were activated by EGF. When cells were stimulated by EGF and irradiated by UV B, the levels of phospho-Akt and phospho-ERK1/2 activated by EGF in E5-expressing cells were about twofold greater than those in LXSN-infected cells. Two other UV-activated stress pathways, p38 and JNK, were activated to the same level during UV B irradiation in both LXSN-infected cells and E5-expressing cells, indicating that E5 protein did not affect these two pathways. After UV B irradiation, p53 was activated in both LXSN-infected cells and E5-expressing cells, and cell cycle analysis showed that nearly all cells in both cell populations were growth arrested. These data suggest that unlike HPV16 E6, which blocks apoptosis by inactivation of p53, HPV16 E5 protects cells from apoptosis by enhancing the PI3K-Akt and ERK1/2 MAPK signal pathways.

This article has been cited by other articles:

• Lewis, D. A., Yi, Q., Travers, J. B., Spandau, D. F (2008). UVB-induced Senescence in Human Keratinocytes Requires a Functional Insulin-like Growth Factor-1 Receptor and p53. Mol. Biol. Cell 19: 1346-1353 [Abstract] [Full Text]  
• Zhang, B., Chen, W., Roman, A. (2006). The E7 proteins of low- and high-risk human papillomaviruses share the ability to target the pRB family member p130 for degradation. Proc. Natl. Acad. Sci. USA 103: 437-442 [Abstract] [Full Text]  
• Disbrow, G. L., Hanover, J. A., Schlegel, R. (2005). Endoplasmic Reticulum-Localized Human Papillomavirus Type 16 E5 Protein Alters Endosomal pH but Not trans-Golgi pH. J. Virol. 79: 5839-5846 [Abstract] [Full Text]  
• Bravo, I. G., Alonso, A. (2004). Mucosal Human Papillomaviruses Encode Four Different E5 Proteins Whose Chemistry and Phylogeny Correlate with Malignant or Benign Growth. J. Virol. 78: 13613-13626 [Abstract] [Full Text]  
• Leykauf, K., Salek, M., Schluter, H., Lehmann, W.-D., Alonso, A. (2004). Identification of membrane proteins differentially expressed in human papillomavirus type 16 E5-transfected human keratinocytes by nanoelectrospray ionization mass spectrometry. J. Gen. Virol. 85: 1427-1431 [Abstract] [Full Text]  
• Cooray, S. (2004). The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival. J. Gen. Virol. 85: 1065-1076 [Abstract] [Full Text]  
• Kabsch, K., Alonso, A. (2002). The Human Papillomavirus Type 16 E5 Protein Impairs TRAIL- and FasL-Mediated Apoptosis in HaCaT Cells by Different Mechanisms. J. Virol. 76: 12162-12172 [Abstract] [Full Text]  
• Hu, J., Han, R., Cladel, N. M., Pickel, M. D., Christensen, N. D. (2002). Intracutaneous DNA Vaccination with the E8 Gene of Cottontail Rabbit Papillomavirus Induces Protective Immunity against Virus Challenge in Rabbits. J. Virol. 76: 6453-6459 [Abstract] [Full Text]