Document Detail


Liberation of functional p53 by proteasome inhibition in human papilloma virus-positive head and neck squamous cell carcinoma cells promotes apoptosis and cell cycle arrest.
MedLine Citation:
PMID:  23421999     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human papilloma virus (HPV) infection represents an emerging risk factor in head and neck squamous cell carcinoma (HNSCC). In contrast to HPV-negative HNSCC, most cases of HPV-positive HNSCC encode wild-type p53, although the p53 protein in these cells is rapidly degraded via HPV E6-mediated ubiquitination and subsequent proteasomal degradation. This unique feature of HPV-positive HNSCC has raised hope that liberation of wild-type p53 from the E6 protein may have therapeutic benefit in this disease. Indeed, suppression of E6 expression promotes apoptosis in HPV-positive HNSCC cell lines. However, the role of p53 in mediating this cell death has not been determined. Here, we demonstrate that siRNAs targeting the E6/E7 RNA, or treatment with the proteasome inhibitor bortezomib, resulted in upregulation of functional p53 and p53 gene targets in three HPV-positive HNSCC cell lines, but not in HPV-negative HNSCC cells. Apoptosis induced by E6/E7 siRNA in HPV-positive cells was found to be dependent on p53, while bortezomib-induced cell death was modestly p53-dependent. Treatment with subtoxic doses of bortezomib led to cell cycle arrest in HPV-positive, but not HPV-negative HNSCC cells. Moreover, this cell cycle arrest was mediated by p53 and the cell cycle inhibitor p21, the product of a p53 target gene. Collectively, these findings establish that wild-type p53 encoded by HPV-positive HNSCC cells, once liberated from HPV E6, can play important roles in promoting apoptosis and cell cycle arrest.
Authors:
Changyou Li; Daniel E Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-19
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  12     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-19     Completed Date:  2013-09-19     Revised Date:  2014-03-26    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  923-34     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Boronic Acids / pharmacology
Carcinoma, Squamous Cell / metabolism*,  virology
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Survival
Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
Head and Neck Neoplasms / metabolism*,  virology
Human papillomavirus 16
Humans
Oncogene Proteins, Viral / genetics*
Papillomavirus E7 Proteins / genetics*
Papillomavirus Infections
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / pharmacology
Pyrazines / pharmacology
RNA Interference
RNA, Messenger / genetics
RNA, Small Interfering
Repressor Proteins / genetics*
Tumor Suppressor Protein p53 / metabolism*
Ubiquitination
Grant Support
ID/Acronym/Agency:
P30 CA047904/CA/NCI NIH HHS; P50 CA097190/CA/NCI NIH HHS; R01 CA137260/CA/NCI NIH HHS; R01 CA137260/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/E6 protein, Human papillomavirus type 16; 0/Oncogene Proteins, Viral; 0/Papillomavirus E7 Proteins; 0/Proteasome Inhibitors; 0/Pyrazines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Repressor Proteins; 0/Tumor Suppressor Protein p53; 0/bortezomib; 0/oncogene protein E7, Human papillomavirus type 16; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections
Comment In:
Cell Cycle. 2013 Mar 15;12(6):868   [PMID:  23442795 ]
Cell Cycle. 2013 Apr 1;12(7):1020-1   [PMID:  23511169 ]

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