Document Detail

Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells.
MedLine Citation:
PMID:  16247456     Owner:  NLM     Status:  MEDLINE    
To investigate whether dysregulation of p53 phosphorylation confers tumor resistance to p53, we analysed the effects of wild-type p53 on oral squamous cell carcinoma (SCC) cell lines carrying various mutations of p53. Introduction of exogenous p53 neither induced apoptosis nor suppressed colony formation in HSC-3 cells lacking any detectable p53 and HSC-4 cells expressing mutant p53R248Q protein. Consistently, exogenous p53 did not induce proapoptotic p53-target genes in these p53-resistant cells. We found that phosphorylation of exogenous p53 on serine 46 (Ser46) was severely impaired in HSC-3 but not HSC-4 cells. A mutant mimicking Ser46-phosphorylation (p53S46D) enhanced proapoptotic Noxa promoter activity, and overcame the resistance to p53-mediated apoptosis and growth suppression in HSC-3 cells. Conversely, a mutant defective for Ser46-phosphorylation (p53S46A) failed to suppress the growth of p53-sensitive HSC-2 cells. In contrast to HSC-3 cells, p53S46D had no effect on HSC-4 cells, and inhibition of endogenous p53R248Q by siRNA restored p53-mediated apoptosis in HSC-4 cells, indicating a dominant-negative effect of p53R248Q protein on wild-type p53 function. These results demonstrate that the defect in Ser46 phosphorylation accounts for the p53 resistance of HSC-3 cells, and provide evidence for a mechanism underlying the acquisition of p53 resistance in oral SCC.
S J A Ichwan; S Yamada; P Sumrejkanchanakij; E Ibrahim-Auerkari; K Eto; M-A Ikeda
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncogene     Volume:  25     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-23     Completed Date:  2006-03-28     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  1216-24     Citation Subset:  IM    
Copyright Information:
Oncogene (2006) 25, 1216-1224. doi:10.1038/sj.onc.1209158; published online 10 October 2005.
Section of Molecular Embryology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
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MeSH Terms
Adenoviridae / genetics
Carcinoma, Non-Small-Cell Lung / genetics,  metabolism
Carcinoma, Squamous Cell / genetics,  metabolism*
Lung Neoplasms / genetics,  metabolism
Mouth Neoplasms / genetics,  metabolism*
Mutation / genetics*
RNA, Small Interfering / pharmacology
Serine / metabolism*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / metabolism*
Reg. No./Substance:
0/RNA, Small Interfering; 0/Tumor Suppressor Protein p53; 56-45-1/Serine

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