Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells
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 form...
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my.iium.irep.41372012-07-16T06:25:25Z http://irep.iium.edu.my/4137/ Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells Arief Ichwan, Solachuddin Jauhari Shumpei, Yamada Piyamas, Sumrejkanchanakij Elza, Ibrahim-Auerkari, K, Eto Ikeda, Masa-Aki R Medicine (General) 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. Nature 2006-02 Article REM application/pdf en http://irep.iium.edu.my/4137/1/1209158a.pdf Arief Ichwan, Solachuddin Jauhari and Shumpei, Yamada and Piyamas, Sumrejkanchanakij and Elza, Ibrahim-Auerkari, and K, Eto and Ikeda, Masa-Aki (2006) Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells. Oncogene, 25 (8). pp. 1216-1224. ISSN 0950-9232 http://www.nature.com/onc/index.html 10.1038/sj.onc.1209158 |
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R Medicine (General) Arief Ichwan, Solachuddin Jauhari Shumpei, Yamada Piyamas, Sumrejkanchanakij Elza, Ibrahim-Auerkari, K, Eto Ikeda, Masa-Aki Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
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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. |
format |
Article |
author |
Arief Ichwan, Solachuddin Jauhari Shumpei, Yamada Piyamas, Sumrejkanchanakij Elza, Ibrahim-Auerkari, K, Eto Ikeda, Masa-Aki |
author_facet |
Arief Ichwan, Solachuddin Jauhari Shumpei, Yamada Piyamas, Sumrejkanchanakij Elza, Ibrahim-Auerkari, K, Eto Ikeda, Masa-Aki |
author_sort |
Arief Ichwan, Solachuddin Jauhari |
title |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
title_short |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
title_full |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
title_fullStr |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
title_full_unstemmed |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
title_sort |
defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells |
publisher |
Nature |
publishDate |
2006 |
url |
http://irep.iium.edu.my/4137/1/1209158a.pdf http://irep.iium.edu.my/4137/ http://www.nature.com/onc/index.html |
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