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Use of Interferon-γ Enzyme-linked Immunospot Assay to Characterize Novel T-cell Epitopes of Human Papillomavirus
Published on: March 8, 2012
Human papillomavirus type 16 E7 oncoprotein inhibits the anaphase promoting complex/cyclosome activity by
1Division of Infectious Diseases, Brigham and Women's Hospital and Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
The anaphase promoting complex/cyclosome (APC/C) is a ubiquitin ligase complex that orchestrates mitotic progression by targeting key mitotic regulators for proteasomal degradation. APC/C dysfunction is a frequent event during cancer development and can give rise to genomic instability. Here we report that the HPV16 E7 oncoprotein interferes with the degradation of APC/C substrates and that the APC/C inhibitor, EMI1, is expressed at higher levels in HPV16 E7-expressing mitotic cells. HPV16 E7 expression causes increased EMI1 mRNA expression and also inhibits EMI1 degradation. The resulting abnormally high EMI1 levels in HPV16 E7-expressing mitotic cells may inhibit degradation of APC/C substrates and cause the prometaphase delay that we have previously observed in such cells.
Insights
The human papillomavirus (HPV) 16 E7 oncoprotein disrupts cell division by increasing levels of the APC/C inhibitor EMI1. This leads to impaired degradation of key cell cycle proteins, causing mitotic errors and genomic instability in cancer.
Area of Science:
- Cell Biology
- Molecular Oncology
- Virology
Background:
- The anaphase-promoting complex/cyclosome (APC/C) is a crucial ubiquitin ligase regulating mitosis.
- APC/C dysfunction contributes to genomic instability and cancer development.
- Human papillomavirus (HPV) oncoproteins are implicated in cervical cancer pathogenesis.
Purpose of the Study:
- To investigate the mechanism by which HPV16 E7 oncoprotein affects APC/C activity.
- To determine the role of the APC/C inhibitor EMI1 in HPV16 E7-mediated cellular effects.
Main Methods:
- Analysis of APC/C substrate degradation in HPV16 E7-expressing cells.
- Quantification of EMI1 mRNA and protein levels.
- Assessment of mitotic progression and prometaphase delay.
Main Results:
- HPV16 E7 expression interferes with the degradation of APC/C substrates.
- EMI1 levels are significantly elevated in HPV16 E7-expressing mitotic cells.
- HPV16 E7 inhibits both EMI1 mRNA degradation and protein degradation, leading to accumulation.
Conclusions:
- HPV16 E7 oncoprotein dysregulates mitosis by increasing EMI1 levels.
- Elevated EMI1 inhibits APC/C activity, leading to prometaphase delay and potential genomic instability.
- This mechanism highlights a novel pathway through which HPV contributes to cancer development.
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