Telomerase activation by the E6 gene product of human papillomavirus type 16.
Activation of telomerase, a ribonucleoprotein complex that synthesizes telomere repeat sequences, is linked to cell immortalization and is characteristic of most cell lines and tumours. Here we show that expression of the human papillomavirus type 16 (HPV-16) E6 protein activates telomerase in early-passage human keratinocytes and mammary epithelial cells. This activation was observed in cells pre-crisis, that is, before they became immortal, and occurred within one passage of retroviral infection with vectors expressing HPV-16 E6. Studies using HPV-16 E6 mutants showed that there was no correlation between the ability of the mutants to activate telomerase and their ability to target p53 for degradation, suggesting that telomerase activation by HPV-16 E6 is p53 independent. Keratinocytes expressing wild-type HPV-16 E6 have an extended lifespan, but do not become immortal, indicating that telomerase activation and E6-mediate degradation of p53 are insufficient for their immortalization. These results show that telomerase activation is an intrinsic, but insufficient, component of transformation by HPV.
Klingelhutz
A J
AJ
Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104, USA.
Foster
S A
SA
McDougall
J K
JK
D001483:Base Sequence; D002460:Cell Line; D002472:Cell Transformation, Viral; D017931:DNA Primers; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes; D008969:Molecular Sequence Data; D009154:Mutation; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D027383:Papillomaviridae / Q000235:genetics / Q000502:physiology*; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017931:DNA Primers; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D019098:Telomerase