HPV-18 E7 conjugates to c-Myc and mediates its transcriptional activity.
Several reports in the literature have indicated that the E6 not only elevates the level of c-Myc level but that the protein also associates with the Myc complex and activates Myc-responsive genes. There would seem to be a mechanism by which this oncogene can modulate cell proliferation and differentiation. Furthermore, an increase in c-Myc levels has also observed during ectopic expression of HPV E7 alone. Using the yeast two-hybrid system, we further found that the c-Myc interacts and forms a specific complex with HPV-16E7. In this study, we have demonstrated that E7 does indeed interact with c-Myc and a sequential deletion analysis of E7 maps the c-Myc interaction site to the carboxyl-terminal region. We determined two HPV-18 E7 binding sites on c-Myc involving the amino acids regions 1-100 and 367-439. The interaction of the high-risk type HPV E7 with c-Myc can augment c-Myc transactivation activity but this does not occur with low-risk type HPV E7. Deletion within the Cys-X-X-Cys repeat motif at the C-terminus of HPV-18 E7 leads to a lost of association with c-Myc and also abolishes the enhancement of c-Myc's transactivation activity. Furthermore, the interaction of HPV-18 E7 with c-Myc functionally promotes c-Myc's DNA-binding ability. Using the hTERT promoter as a model, enhanced c-Myc binding ability to the hTERT promoter as measured by immunoprecipitation assay was observed and occurred in an E7 dose-dependent manner. Taken together, these results provide significant new insights into the association of c-Myc with E7 and the possible involvement of high-risk E7 in oncogenesis.
Wang
Yi-Wei
YW
National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan, ROC.
Chang
Hung-Shu
HS
Lin
Ching-Hui
CH
Yu
Winston C Y
WC
D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D017353:Gene Deletion; D006367:HeLa Cells; D052161:Human papillomavirus 18 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016296:Mutagenesis; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques
D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase