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The Effect of Proteasome Inhibition on p53 Degradation and Proliferation in Tonsil Epithelial Cells
George F. Harris IV, MD;
Mary E. Anderson;
John H. Lee, MD
Arch Otolaryngol Head Neck Surg. 2008;134(2):157-163.
Objective To determine whether proteasome inhibition could reverse E6-mediated p53 degradation, cause selective growth inhibition, and induce apoptosis in human papillomavirus E6-transformed primary tonsil epithelial cells.
Design Primary human and mouse tonsil epithelial cell lines were transformed with a retrovirus containing human papillomavirus 16 oncogenes. MG132 was used to inhibit proteasome degradation in vitro and in vivo, and biochemical assays regarding p53 and apoptosis were performed.
Results In cells that express E6, proteasome inhibition with MG132 restored p53 protein levels and decreased proliferation in a dose-dependent fashion that was significantly more pronounced compared with controls. However, inhibition of proliferation occurred at a lower concentration than restoration of p53 protein expression. Also, wild-type and p53 knockout mouse tonsil epithelial cells that express E6 had near-identical inhibition of growth, suggesting that growth inhibition was p53 independent. In vivo studies did not demonstrate any growth inhibition.
Conclusion The findings suggest that proteasome inhibition preferentially inhibits proliferation in cells expressing E6 through a p53-independent mechanism.
Author Affiliations: Department of Otolaryngology–Head and Neck Surgery, The University of Iowa, Iowa City (Drs Harris and Lee); and Department of Otolaryngology, US Department of Veterans Affairs, Veterans Health Administration, Iowa City (Ms Anderson and Dr Lee).
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