title: Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells.
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.
authors.affiliation: Section of Molecular Embryology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: S J A
authors.initials: SJ
authors.lastname: Ichwan
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: P
authors.initials: P
authors.lastname: Sumrejkanchanakij
authors.forename: E
authors.initials: E
authors.lastname: Ibrahim-Auerkari
authors.forename: K
authors.initials: K
authors.lastname: Eto
authors.forename: M-A
authors.initials: MA
authors.lastname: Ikeda
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D012694:Serine