Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways.
Single base pair mutations that alter the function of tumor suppressor genes and oncogenes occur frequently during oncogenesis. The guardian of the genome, p53, is inactivated by point mutation in more than 50% of human cancers. Synthetic small inhibiting RNAs (siRNAs) can suppress gene expression in mammalian cells, although their degree of selectivity might be compromised by an amplification mechanism. Here, we demonstrate that a single base difference in siRNAs discriminates between mutant and WT p53 in cells expressing both forms, resulting in the restoration of WT protein function. Therefore, siRNAs may be used to suppress expression of point-mutated genes and provide the basis for selective and personalized antitumor therapy.
Martinez
Luis Alfonso
LA
Unité Propre de Recherche 9079, Centre National de la Recherche Scientifique-Ligue Nationale Contre le Cancer, Institut André Lwoff, 7 Rue Guy Moquet, 94800 Villejuif, France.
Naguibneva
Irina
I
Lehrmann
Heike
H
Vervisch
Arlette
A
Tchénio
Thierry
T
Lozano
Guillermina
G
Harel-Bellan
Annick
A
D001483:Base Sequence; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D009154:Mutation; D017354:Point Mutation; D034741:RNA, Small Interfering / Q000138:chemical synthesis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53