5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction.
5-fluorouracil (5-FU) is a widely used chemotherapeutic drug for the treatment of a variety of solid tumors. The anti-tumor 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.
Mesh Terms:
Antimetabolites, Antineoplastic, Apoptosis, Cell Line, Tumor, Fluorouracil, G1 Phase, Humans, Mitochondrial Proteins, Models, Biological, Protein Binding, Proto-Oncogene Proteins c-mdm2, Ribosomal Proteins, Ribosomes, S Phase, Tumor Suppressor Protein p53
Antimetabolites, Antineoplastic, Apoptosis, Cell Line, Tumor, Fluorouracil, G1 Phase, Humans, Mitochondrial Proteins, Models, Biological, Protein Binding, Proto-Oncogene Proteins c-mdm2, Ribosomal Proteins, Ribosomes, S Phase, Tumor Suppressor Protein p53
J. Biol. Chem.
Date: Mar. 16, 2007
PubMed ID: 17242401
View in: Pubmed Google Scholar
Download Curated Data For This Publication
145191
Switch View:
- Interactions 6
- PTM Genes 1