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

• 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/4137/1/1209158a.pdf; http://irep.iium.edu.my/4137/; http://www.nature.com/onc/index.html
• Institution: Universiti Islam Antarabangsa Malaysia

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.