| RRC ID |
12038
|
| 著者 |
Ichwan SJ, Yamada S, Sumrejkanchanakij P, Ibrahim-Auerkari E, Eto K, Ikeda MA.
|
| タイトル |
Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells.
|
| ジャーナル |
Oncogene
|
| Abstract |
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.
|
| 巻・号 |
25(8)
|
| ページ |
1216-24
|
| 公開日 |
2006-2-23
|
| DOI |
10.1038/sj.onc.1209158
|
| PII |
1209158
|
| PMID |
16247456
|
| MeSH |
Adenoviridae / genetics
Apoptosis
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / metabolism*
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Mouth Neoplasms / genetics
Mouth Neoplasms / metabolism*
Mutation / genetics*
Phosphorylation
RNA, Small Interfering / pharmacology
Serine / metabolism*
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / metabolism*
|
| IF |
7.971
|
| 引用数 |
40
|
|
WOS 分野
|
GENETICS & HEREDITY
ONCOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| 遺伝子材料 |
AxCAhp53WT (forward) (RDB02755) |
| ヒト・動物細胞 |
HSC-3(RCB1975)
HSC-2(RCB1945)
HSC-4(RCB1902)
A549(RCB0098) |
