UVB irradiation reduces the half-life and transactivation potential of the human papillomavirus 16 E2 protein.
Human papillomaviruses (HPV) are causative agents of human cancers including those of the cervix and also of the head and neck; HPV16 is the most commonly found type in these diseases. The viral E2 protein regulates transcription from the viral genome by interacting with DNA-binding sequences in the HPV transcriptional control region; it also regulates replication by interacting with and recruiting the HPV replication factor E1 to the viral origin. Therefore, E2 is essential for the viral life cycle. The E2 protein interacts with several proteins involved in the cellular response to DNA damage including p53, TopBP1, and PARP. We therefore set out to establish whether DNA-damaging agents can regulate E2 activity. Here we show that UVB irradiation downregulates transcriptional activity of both HPV16 and HPV8 E2, while hydroxyurea and etoposide do not. This downregulation of E2 activity is independent of p53 function as it occurs in p53 wild type and null cell types as well as in the presence of functional HPV16 E6 that degrades p53. Using stable cell lines expressing E2 we show that this downregulation of E2 function by UVB is due to a reduction of the E2 protein half-life. The identification of the pathway(s) through which UVB downregulates E2 transcriptional activity and protein levels will present a novel target for the treatment of HPV-related diseases.
Taylor
Ewan R
ER
Department of Veterinary Pathology, Institute of Comparative Medicine, University of Glasgow, Garscube Estate, Bearsden Road, Glasgow G61 1QH, Scotland, UK.
Boner
Winifred
W
Dornan
Edward S
ES
Corr
Eilidh M
EM
Morgan
Iain M
IM
D000970:Antineoplastic Agents / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000528:radiation effects; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009856:Oncogene Proteins, Viral / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015533:Transcriptional Activation / Q000528:radiation effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C054855:E2 protein, Human papillomavirus type 16; D007976:Leupeptins; D009856:Oncogene Proteins, Viral; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C468298:oncogene protein E2, Human papillomavirus type 8; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde