Review Modulation of apoptosis by early human papillomavirus proteins in cervical cancer A. Lagunas-Martínez a , V. Madrid-Marina a , P. Gariglio b, ⁎ a Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México b Departamento de Genética y Biología Molecular, CINVESTAV-IPN, Av. IPN 2508 Col. San Pedro Zacatenco, C. P. 07360., D.F., México abstract article info Article history: Received 21 December 2008 Received in revised form 24 March 2009 Accepted 29 March 2009 Available online 15 April 2009 Keywords: HPV E6 E7 Apoptosis TNF-α CD95 Cervical cancer (CC) constitutes a major women health problem. Clinical, molecular, and epidemiological investigations have identified persistent infection with high risk human papillomavirus (HR-HPV) as the major cause of CC. HR-HPVs lead to development of cervical carcinoma, predominantly through the action of E5, E6 and E7 viral oncoproteins. After HR-HPV infection, viral proteins employ strategies to modulate apoptosis. The E2 viral protein induces apoptosis in both normal and HPV-transformed cells through activation of caspase-8. The E5 protein can impair CD95L- and TRAIL-mediated apoptosis, which suggests that it may prevent apoptosis at early stages of viral infection. E6 inhibits apoptosis through the proteolytic inactivation of pro-apoptotic proteins such as p53, FADD, or procaspase-8, employing the ubiquitin proteasome pathway, or through interactions with proteins that form the death-inducing signaling complex (DISC) such as TNF-R1. On the other hand, E7 oncoprotein expressing cells are usually predisposed to undergo apoptosis. Useful targets for therapeutic strategies would interfere with expression or function of HR-HPV proteins to eliminate cells that express viral oncoproteins. In this review, we summarize the available data on the interaction of early HPV proteins with cellular factors that promote cell death, and the functional consequences of these interactions on apoptosis. © 2009 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2. The apoptotic pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3. HPV proteins and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1. E2-induced apoptosis in several cell lines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.2. Inhibition of apoptosis by E5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.3. The role of E6 in apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.4. E7 and apoptosis induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.5. Induction of cell death and growth control of cervical cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1. Introduction Cervical cancer (CC) and precancerous cervical lesions constitute a major women health problem. Clinical, molecular, and epidemiological investigations have identified high risk human papillomavirus (HR- HPV) as the major cause of CC and cervical dysplasia [1]. Papillo- mavirus are small DNA viruses that infect various epithelial tissues, replicate in the stratified layers of skin and mucosa, and usually give rise to benign lesions such as warts or papillomas. HPVs can be classified as either HR-HPV or low risk types (LR-HPV) on the basis of their genital clinical associations. The HR-HPV types, such as HPV-16 and 18 are commonly associated with lesions that can progress to high grade intraepithelial neoplasia and ultimately to carcinoma, while the LR-HPV types, such as HPV-6 and 11 are found associated primarily with benign genital lesions, which rarely progress to cancer [2]. HR-HPVs code for at least three proteins with growth-stimulating and transforming properties (E5, E6, and E7). E5 protein contributes to cellular transformation by increasing the mitogenic stimulus from Biochimica et Biophysica Acta 1805 (2010) 6–16 ⁎ Corresponding author. Tel.: +52 55 5747 33 37; fax: +52 55 5747 39 31. E-mail address: vidal@cinvestav.mx (P. Gariglio). 0304-419X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbcan.2009.03.005 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbacan