Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y).
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 p21(waf1). Additional molecular modeling data highlighted the structural similarities between p53(C238Y) and wild-type p53, further supporting that the p53(C238Y) mutant still retains functional wild-type p53 properties.
Ferrone
Marco
M
Molecular Simulation Engineering Laboratory, Department of Chemical Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
Perrone
Federica
F
Tamborini
Elena
E
Paneni
Maria Silvia
MS
Fermeglia
Maurizio
M
Suardi
Simona
S
Pastore
Elisa
E
Delia
Domenico
D
Pierotti
Marco A
MA
Pricl
Sabrina
S
Pilotti
Silvana
S
D000328:Adult; D015139:Blotting, Southern; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005784:Gene Amplification / Q000502:physiology; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018317:Nerve Sheath Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2