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HPV-16 E6 oncoprotein induces mutations via p53-dependent and -independent pathways
1Dental Research Institute, School of Dentistry, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1668, USA.
Oncology Reports
|June 16, 2000
Summary
High-risk human papillomaviruses (HPV) E6 oncoprotein drives cancer by affecting tumor suppressor p53. This study reveals E6 also causes mutations through p53-independent pathways, highlighting broader oncogenic mechanisms.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- High-risk human papillomaviruses (HPV) E6 oncoprotein is linked to oncogenesis.
- E6 promotes cancer by inactivating the tumor suppressor protein p53 through binding and degradation.
Purpose of the Study:
- To investigate if p53 inactivation is the sole mechanism for E6-induced oncogenesis.
- To determine the role of p53-dependent and -independent pathways in E6-induced mutagenicity.
Main Methods:
- Constructed plasmid vectors expressing wild-type (wt) and mutant (mt) HPV E6 proteins.
- Transfected RKO cells (expressing wt p53) with E6 plasmids and challenged with DNA damaging agents.
- Assessed p53 levels and measured mutation frequency at the hprt locus.
Main Results:
- DNA damaging agents increased p53 levels in control and mt E6 cells incapable of binding p53, but not in cells with mt E6 that bind p53.
- Both wt E6 and mt E6 (binding or non-binding to p53) significantly increased hprt locus mutation frequency compared to controls.
- The mutagenicity elevation by mt E6 was comparable to that of wt E6.
Conclusions:
- HPV E6 oncoprotein induces mutagenicity through both p53 inactivation and p53-independent pathways.
- E6's oncogenic potential extends beyond p53 targeting, involving alternative mechanisms.
- Understanding these pathways is crucial for developing targeted cancer therapies.