Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis.
Inhibition of apoptosis plays an important role in the cellular immortalization and transformation induced by E6 and E7 oncoproteins of human papillomavirus (HPV). Here, we report that the transcription of the inhibitor of apoptosis gene, cellular inhibitor of apoptosis protein 2, (c-IAP2), is significantly upregulated in HPV16 E6/E7-immortalized human oral keratinocytes (HOK16E6E7). Overexpression of E6/E7 from the high-risk HPV16 or 18, but not from the low-risk HPV6, activated c-IAP2 promoter. E6 from HPV16 and 18 played a major role in the activation. In addition, the induction of c-IAP2 transcription required nuclear factor-kappaB activity. Overexpression of c-IAP2 in normal human oral keratinocyte conferred resistance to tumor necrosis factor-alpha (TNF-alpha)/cycloheximide (CHX)-induced apoptosis, suggesting the increased c-IAP2 expression in HOK16E6E7 may protect the cells from TNF-alpha-mediated cell death. Moreover, depletion of endogenous c-IAP2 using RNA interference in HOK16E6E7 induced apoptosis, indicating that c-IAP2 is necessary for HPV16 E6/E7-induced resistance to apoptosis and cell survival. Of note, high levels of c-IAP2 transcription were found in several HPV16- or HPV18-positive cancer cells, and depletion of c-IAP2 caused cell death in HPV18-positive HeLa cells. Thus, upregulation of c-IAP2 by E6 and E7 may confer resistance to apoptosis that is necessary for sustained growth of some HPV16- and HPV18-positive cancer cells.
Yuan
Huidong
H
Department of Oral & Maxillofacial Surgery, Charles R Drew University of Medicine & Science, Los Angeles, CA 90059, USA.
Fu
Fenghua
F
Zhuo
Jiaying
J
Wang
Wei
W
Nishitani
Junko
J
An
Dong Sung
DS
Chen
Irvin S Y
IS
Liu
Xuan
X
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018929:Cell Culture Techniques; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D005881:Gingiva / Q000166:cytology / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D027383:Papillomaviridae / Q000502:physiology*; D050725:Papillomavirus E7 Proteins; D010957:Plasmids; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000502:physiology
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011506:Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D011505:Protein-Tyrosine Kinases