HPV E6 protein interacts physically and functionally with the cellular telomerase complex.
Telomerase activation is critical for the immortalization of primary human keratinocytes by the high-risk HPV E6 and E7 oncoproteins, and this activation is mediated in part by E6-induction of the hTERT promoter. E6 induces the hTERT promoter via interactions with the cellular ubiquitin ligase, E6AP, and with the c-Myc and NFX-1 proteins, which are resident on the promoter. In the current study we demonstrate that E6 protein interacts directly with the hTERT protein. Correlating with its ability to bind hTERT, E6 also associates with telomeric DNA and with endogenous active telomerase complexes. Most importantly, E6 increases the telomerase activity of human foreskin fibroblasts transduced with the hTERT gene, and this activity is independent of hTERT mRNA expression. Unlike its ability to degrade p53, E6 does not degrade hTERT protein in vitro or in vivo. Our studies of E6/hTERT interactions also reveal that the C-terminal tagged hTERT protein, although incapable of immortalizing fibroblasts, does immortalize keratinocytes in collaboration with the viral E7 protein. Thus, E6 protein mediates telomerase activation by a posttranscriptional mechanism and these findings provide a model for exploring the direct modulation of cell telomerase/telomere function by an oncogenic virus and suggest its potential role in both neoplasia and virus replication.
Department of Pathology, Georgetown University Medical School, 3900 Reservoir Road, Washington, DC 20057, USA.
Xuefeng
X
Liu
Aleksandra
A
Dakic
Yiyu
Y
Zhang
Yuhai
Y
Dai
Renxiang
R
Chen
Richard
R
Schlegel
D001483:Base Sequence; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000201:enzymology; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology*; D008297:Male; D008954:Models, Biological; D027383:Papillomaviridae / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000378:metabolism*
D014764:Viral Proteins; C509186:TERT protein, human; D019098:Telomerase