Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells

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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Main Authors: Arief Ichwan, Solachuddin Jauhari, Shumpei, Yamada, Piyamas, Sumrejkanchanakij, Elza, Ibrahim-Auerkari, K, Eto, Ikeda, Masa-Aki
Format: Article
Language:English
Published: Nature 2006
Subjects:
R Medicine (General)
Online Access:http://irep.iium.edu.my/4137/
http://irep.iium.edu.my/4137/
http://irep.iium.edu.my/4137/
http://irep.iium.edu.my/4137/1/1209158a.pdf
id iium-4137
recordtype eprints
spelling iium-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 PeerReviewed 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
repository_type Digital Repository
institution_category Local University
institution International Islamic University Malaysia
building IIUM Repository
collection Online Access
language English
topic R Medicine (General)
spellingShingle 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
description 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/
http://irep.iium.edu.my/4137/
http://irep.iium.edu.my/4137/
http://irep.iium.edu.my/4137/1/1209158a.pdf
first_indexed 2023-09-18T20:12:15Z
last_indexed 2023-09-18T20:12:15Z
_version_ 1777407555400630272

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