Journal
ONCOGENE
Volume 24, Issue 32, Pages 5069-5078Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208691
Keywords
apoptosis; c-IAP2; upregulation; human papillomavirus; oral keratinocyte
Funding
- NCRR NIH HHS [G12-RR03026-15] Funding Source: Medline
- NIDCR NIH HHS [K23 DE00430] Funding Source: Medline
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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-kappa B 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.
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