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The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional
H Zimmermann1, R Degenkolbe, H U Bernard
1Institute of Molecular and Cell Biology, Singapore 117 609, Singapore.
Abstract:
The transforming proteins of the small DNA tumor viruses, simian virus 40 (SV40), adenovirus, and human papillomavirus (HPV) target a number of identical cellular regulators whose functional abrogation is required for transformation. However, while both adenovirus E1A and SV40 large T transforming properties also depend on the targeting of the transcriptional coactivator CBP/p300, no such interaction has been described for the HPV oncoprotein E6 or E7. Here, we demonstrate that the HPV-16 E6 protein, previously shown to facilitate the degradation of p53 in a complex with E6-associated protein (E6AP), also targets CBP/p300 in an interaction involving the C-terminal zinc finger of E6 and CBP residues 1808 to 1826. Furthermore, this interaction is limited to E6 proteins of high-risk HPVs associated with cervical cancer that have the capacity to repress p53-dependent transcription. An HPV-16 E6 mutant (L50G) that binds CBP/p300, but not E6AP, is still capable of down-regulating p53 transcriptional activity. Thus, HPV E6 proteins possess two distinct mechanisms by which to abrogate p53 function: the repression of p53 transcriptional activity by targeting the p53 coactivator CBP/p300, and the removal of cellular p53 protein through the proteosome degradation pathway.
Insights
Human papillomavirus (HPV) oncoprotein E6 targets CBP/p300, a key regulator, in addition to degrading p53. This dual mechanism, involving high-risk HPV E6, represses p53 transcription and aids cellular transformation.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Small DNA tumor viruses utilize transforming proteins to disrupt cellular regulators for transformation.
- Adenovirus E1A and SV40 large T proteins target CBP/p300, but HPV oncoproteins E6/E7 interactions with CBP/p300 were undescribed.
Purpose of the Study:
- To investigate if HPV oncoprotein E6 interacts with the transcriptional coactivator CBP/p300.
- To elucidate the mechanism by which HPV-16 E6 affects p53 function and transcriptional activity.
Main Methods:
- Demonstrated HPV-16 E6 interaction with CBP/p300 using specific binding assays.
- Utilized HPV-16 E6 mutants to dissect the roles of E6AP and CBP/p300 interactions in p53 regulation.
Main Results:
- HPV-16 E6 directly targets CBP/p300 via its C-terminal zinc finger.
- This interaction is specific to high-risk HPV E6 proteins associated with cervical cancer.
- An HPV-16 E6 mutant binding CBP/p300 but not E6AP retained the ability to down-regulate p53 activity.
Conclusions:
- HPV E6 employs two distinct mechanisms to abrogate p53 function: CBP/p300 targeting and p53 degradation via E6AP.
- Targeting CBP/p300 by HPV E6 represses p53-dependent transcription, contributing to cellular transformation.