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

Oncogene volume 25, pages 1216–1224 (2006)Cite this article

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.

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Acknowledgements

We thank Nobuyuki Tanaka (Nippon Medical School, Japan) for materials, and Junko Hashimoto for technical assistance. This study was supported in part by Grants-in-Aid for Scientific Research (16209054 to MI) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Section of Molecular Embryology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    S J A Ichwan, S Yamada, K Eto & M-A Ikeda

  2. Section of Maxillofacial Surgery, Maxillofacial Reconstruction and Function, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    S Yamada

  3. Department of Anatomy, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand

    P Sumrejkanchanakij

  4. Department of Oral Biology, Faculty of Dentistry, University of Indonesia, Jakarta, Indonesia

    E Ibrahim-Auerkari

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  1. S J A Ichwan
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  2. S Yamada
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Correspondence to M-A Ikeda.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc).

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Ichwan, S., Yamada, S., Sumrejkanchanakij, P. et al. Defect in serine 46 phosphorylation of p53 contributes to acquisition of p53 resistance in oral squamous cell carcinoma cells. Oncogene 25, 1216–1224 (2006). https://doi.org/10.1038/sj.onc.1209158

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