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.
Sun
Xiao-Xin
XX
Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.
Dai
Mu-Shui
MS
Lu
Hua
H
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000494:pharmacology*; D016193:G1 Phase; D006801:Humans; D024101:Mitochondrial Proteins / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins / Q000378:metabolism; D012270:Ribosomes / Q000737:chemistry*; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; C097584:MRPL23 protein, human; D024101:Mitochondrial Proteins; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C029742:ribosomal protein L5; D051736:Proto-Oncogene Proteins c-mdm2; D005472:Fluorouracil