Modulation of apoptosis by early human papillomavirus proteins in cervical cancer.
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.
Dirección de Infecciones Crónicas y Cáncer, Centro de Investigación sobre Enfermedades Infecciosas, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México.
A
A
Lagunas-Martínez
V
V
Madrid-Marina
P
P
Gariglio
D017209:Apoptosis / Q000502:physiology*; D005260:Female; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D027383:Papillomaviridae / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000473:pathology / Q000821:virology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology*
D009856:Oncogene Proteins, Viral