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Mutant p53 is constitutively phosphorylated at Serine 15 in UV-induced mouse skin tumors: involvement of ERK1/2 MAP kinase

Oncogene volume 22, pages 5958–5966 (2003)Cite this article

Abstract

Upon DNA damage, phosphorylation and nuclear translocation of wild-type p53 tumor suppressor protein signals its functional activation. However, very little is known about phosphorylation and localization of mutant p53. We found that mutant p53 protein in UV-induced murine primary skin tumors and cultured cell lines was constitutively phosphorylated at serine 15 residue and localized in the cell's nuclei. To investigate the mechanism of constitutive phosphorylation of mutant p53, we tested the involvement of a wide range of protein kinases and found that ERK1/2 mitogen-activated protein kinase was physically associated with mutant p53 in the nucleus. Addition of active recombinant ERK2 kinase protein in vitro to immunoprecipitated mutant p53 resulted in increased phosphorylation at serine 15. Furthermore, ERK1/2 activity was higher in tumor cells than normal cells, suggesting that phosphorylation of mutant p53 at serine 15 depends on the level of ERK1/2 activation. Interestingly, accumulation of mutant p53 in tumor cells was paralleled by low levels of Murine Double Minute 2 protein (MDM2) expression. However, when MDM2 was overexpressed, the fraction of mutant p53 that was phosphorylated at serine 15 resisted degradation, whereas the level of total p53 decreased, suggesting that phosphorylation at serine 15 and downregulation of MDM2 protein may both contribute to stabilization of mutant p53 in tumor cells.

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Acknowledgements

We thank Dr Guillermina Lozano for the MDM2 expression vector. This work was supported by National Cancer Institute grant CA 46523 (HN Ananthaswamy) and The University of Texas MD Anderson Cancer Center institutional core grant CA 16672.

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  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 178, Houston, 77030-4009, TX, USA

    Vladislava O Melnikova, Annette B Santamaria, Svetlana V Bolshakov & Honnavara N Ananthaswamy

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  1. Vladislava O Melnikova
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  2. Annette B Santamaria
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  4. Honnavara N Ananthaswamy
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Correspondence to Honnavara N Ananthaswamy.

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Melnikova, V., Santamaria, A., Bolshakov, S. et al. Mutant p53 is constitutively phosphorylated at Serine 15 in UV-induced mouse skin tumors: involvement of ERK1/2 MAP kinase. Oncogene 22, 5958–5966 (2003). https://doi.org/10.1038/sj.onc.1206595

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