5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction

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122 Scopus citations

Abstract

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug for the treatment of a variety of solid tumors. The antitumor activity of 5-FU has been attributed in part to its ability to induce p53-dependent cell growth arrest and apoptosis. However, the molecular mechanisms underlying p53 activation by 5-FU remain largely obscure. Here we report that 5-FU treatment leads to p53 stabilization and activation by blocking MDM2 feedback inhibition through ribosomal proteins. 5-FU treatment increased the fraction of ribosome-free L5, L11, and L23 ribosomal proteins and their interaction with MDM2, leading to p53 activation and G1/S arrest. Conversely, individual knockdown of these ribosomal proteins by small interfering RNA prevented the 5-FU-induced p53 activation and reversed the 5-FU-induced G1/S arrest. These results demonstrate that 5-FU treatment triggers a ribosomal stress response so that ribosomal proteins L5, L11, and L23 are released from ribosome to activate p53 by ablating the MDM2-p53 feedback circuit.

Original languageEnglish (US)
Pages (from-to)8052-8059
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number11
DOIs
StatePublished - Mar 16 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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