The regulatory E2 proteins of human genital papillomaviruses are pro-apoptotic.
Cervical carcinomas are frequently associated with infection by human papillomaviruses (HPVs). These viruses encode two oncogenes E6 and E7, which promote cell proliferation and immortalization. The viral E2 protein represses transcription of the E6/E7 oncogenes and activates viral DNA replication together with the viral E1 helicase. The E2 protein is specifically inactivated in HPV18-associated carcinoma, suggesting that it may prevent carcinogenic progression. Indeed, E2 was shown to exhibit a strong anti-proliferative action when ectopically expressed in cervical carcinoma cells, as it induces both G1 cell cycle arrest and cell death by apoptosis. While the cell cycle arrest is due to E2-mediated transcriptional repression of the viral oncogenes, the induction of apoptosis appears to be an autonomous function of E2. The amino-terminal transactivation domain (TAD) of the E2 protein is required for its pro-apoptotic activity, but transcriptional transactivation is not involved. E2 induces apoptosis through the extrinsic pathway, involving the initiator caspase 8. In addition, E2 is cleaved by caspases during apoptosis, providing an example of an apoptotic inducer, which is itself a target for caspase cleavage. The cleaved E2 protein exhibits an enhanced apoptotic activity, suggesting that it may participate in an amplification loop. This article reviews our current knowledge of the pro-apoptotic activity of the oncogenic papillomavirus E2 proteins, and discusses the implications for the viral vegetative cycle.
Blachon
S
S
Unit of Gene Expression and Diseases, URA 1644 of CNRS, Institut Pasteur, 25, rue du Dr Roux, 75724 Paris cedex 15, France.
Demeret
C
C
D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D027383:Papillomaviridae / Q000378:metabolism / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D009856:Oncogene Proteins, Viral; D016159:Tumor Suppressor Protein p53; C069102:oncogene protein E2, Human papillomavirus type 18; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases