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Cell cycle-dependent disruption of E2F-p107 complexes by human papillomavirus type 16 E7
K Zerfass1, L M Levy, C Cremonesi
1Imperial Cancer Research Fund Tumour Virus Group, Department of Pathology, University of Cambridge, UK.
Abstract:
The human papillomavirus type 16 (HPV-16) E7 and adenovirus (Ad) E1A oncoproteins share a common pathway of transformation. They disrupt the cell cycle G1 phase-specific protein complex containing the E2F transcription factor and the regulatory protein Rb1, the retinoblastoma tumour suppressor gene product. In the G1 and S phases of the cell cycle, E7 and E1A bind two other cellular complexes containing the Rb1-related protein p107 and E2F. Ad E1A disrupts both complexes and releases active E2F. In contrast, HPV-16 E7, although it efficiently binds both E2F-p107 complexes, causes dissociation of the G1 phase complex only. Using chimeric proteins of HPV-16 E7 and Ad E1A we were able to demonstrate that the ability of E1A to disrupt both G1 and S phase E2F-p107 complexes is not due to the higher concentration of Ad E1A in the cell, but is an intrinsic property of the Ad E1A transforming region. These data suggest that E1A and E7 may function in cellular transformation in similar, but not identical ways.
Insights
Human papillomavirus type 16 (HPV-16) E7 and adenovirus (Ad) E1A oncoproteins disrupt cell cycle regulation. While both bind E2F-p107 complexes, Ad E1A disrupts both G1 and S phase complexes, unlike HPV-16 E7.
Area of Science:
- Oncology
- Molecular Biology
- Virology
Background:
- Human papillomavirus type 16 (HPV-16) E7 and adenovirus (Ad) E1A oncoproteins are key viral transforming proteins.
- Both oncoproteins target the retinoblastoma tumor suppressor protein (Rb1) and related proteins, disrupting cell cycle control.
Purpose of the Study:
- To compare the mechanisms by which HPV-16 E7 and Ad E1A disrupt cellular complexes containing Rb1-related proteins and E2F transcription factors.
- To elucidate the specific regions of Ad E1A responsible for its distinct activity.
Main Methods:
- Utilized chimeric proteins constructed from HPV-16 E7 and Ad E1A.
- Analyzed the disruption of G1 and S phase specific E2F-p107 complexes.
Main Results:
- HPV-16 E7 and Ad E1A bind to cellular complexes containing Rb1-related protein p107 and E2F.
- Ad E1A disrupts both G1 and S phase E2F-p107 complexes, releasing active E2F, while HPV-16 E7 primarily disrupts the G1 phase complex.
- Chimeric protein analysis revealed that the Ad E1A transforming region intrinsically confers the ability to disrupt both G1 and S phase complexes.
Conclusions:
- Ad E1A and HPV-16 E7 share common pathways in cellular transformation but exhibit distinct mechanisms in disrupting cell cycle regulatory complexes.
- The transforming region of Ad E1A possesses intrinsic properties enabling broader disruption of E2F-p107 complexes compared to HPV-16 E7.