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

Research output: Contribution to journalArticle

112 Citations (Scopus)

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

Fingerprint

Ribosomal Proteins
Fluorouracil
Chemical activation
Ribosomes
Feedback
Cell growth
Small Interfering RNA
Tumors
Stabilization
Apoptosis
Networks (circuits)
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry

Cite this

5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction. / Sun, Xiao-Xin; Dai, Mushui; Lu, Hua.

In: Journal of Biological Chemistry, Vol. 282, No. 11, 16.03.2007, p. 8052-8059.

Research output: Contribution to journalArticle

@article{980603df2c05406e96f851b297c019c0,
title = "5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction",
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.",
author = "Xiao-Xin Sun and Mushui Dai and Hua Lu",
year = "2007",
month = "3",
day = "16",
doi = "10.1074/jbc.M610621200",
language = "English (US)",
volume = "282",
pages = "8052--8059",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "11",

}

TY - JOUR

T1 - 5-fluorouracil activation of p53 involves an MDM2-ribosomal protein interaction

AU - Sun, Xiao-Xin

AU - Dai, Mushui

AU - Lu, Hua

PY - 2007/3/16

Y1 - 2007/3/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34247204753&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34247204753&partnerID=8YFLogxK

U2 - 10.1074/jbc.M610621200

DO - 10.1074/jbc.M610621200

M3 - Article

C2 - 17242401

AN - SCOPUS:34247204753

VL - 282

SP - 8052

EP - 8059

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 11

ER -