Functional analysis and molecular modeling show a preserved wild-type activity of p53C238Y

Marco Ferrone, Federica Perrone, Elena Tamborini, Maria Silvia Paneni, Maurizio Fermeglia, Simona Suardi, Elisa Pastore, Domenico Delia, Marco A. Pierotti, Sabrina Pricl, Silvana Pilotti

Research output: Contribution to journalArticle

Abstract

In human tumors, p53 is often disabled by mutations in its DNA-binding domain and is thus inactive as a transcription factor. Alternatively, MDM2 gene amplification or up-regulation represents a mechanism of p53 wild-type inactivation, mainly reported in soft tissue sarcomas. In a previous TP53 analysis carried out on sporadic and NF1-related malignant peripheral nerve sheath tumors, in two cases, we observed the occurrence of C238Y missense mutation, leading to p53 stabilization unexpectedly coupled with immunophenotypic MDM2 overexpression. To investigate this TP53 missense mutation not yet functionally characterized in mammalian cell, we did MDM2 Southern blot and p53 C238Y /MDM2 biochemical and functional analyses followed by molecular modeling. The results showed a lack of MDM2 gene amplification, evidence of p53-MDM2 protein complexes, and presence of a p53 that retains the ability to become phosphorylated on Ser15 and to induce the transcription of p2lwaf1. Additional molecular modeling data highlighted the structural similarities between p53C238Y and wild-type p53, further supporting that the p53C238Y mutant still retains functional wild-type p53 properties.

Original languageEnglish
Pages (from-to)1467-1473
Number of pages7
JournalMolecular Cancer Therapeutics
Volume5
Issue number6
DOIs
Publication statusPublished - Jun 2006

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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    Ferrone, M., Perrone, F., Tamborini, E., Paneni, M. S., Fermeglia, M., Suardi, S., Pastore, E., Delia, D., Pierotti, M. A., Pricl, S., & Pilotti, S. (2006). Functional analysis and molecular modeling show a preserved wild-type activity of p53C238Y . Molecular Cancer Therapeutics, 5(6), 1467-1473. https://doi.org/10.1158/1535-7163.MCT-06-0012