Synthetic small inhibiting RNAs: efficient tools to inactivate oncogenic mutations and restore p53 pathways

Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14849-54. doi: 10.1073/pnas.222406899. Epub 2002 Oct 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Gene Expression Regulation, Neoplastic*
  • Genes, p53*
  • Humans
  • Mutation
  • Point Mutation*
  • RNA, Small Interfering / chemical synthesis
  • RNA, Small Interfering / genetics*
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • RNA, Small Interfering
  • Tumor Suppressor Protein p53