Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.
Increases in p53 protein levels after DNA damage have largely been attributed to an increase in the half-life of p53 protein. Here we demonstrate that increased translation of p53 mRNA is also a critical step in the induction of p53 protein in irradiated cells. Ribosomal protein L26 (RPL26) and nucleolin were found to bind to the 5' untranslated region (UTR) of p53 mRNA and to control p53 translation and induction after DNA damage. RPL26 preferentially binds to the 5'UTR after DNA damage, and its overexpression enhances association of p53 mRNA with heavier polysomes, increases the rate of p53 translation, induces G1 cell-cycle arrest, and augments irradiation-induced apoptosis. Opposite effects were seen when RPL26 expression was inhibited. In contrast, nucleolin overexpression suppresses p53 translation and induction after DNA damage, whereas nucleolin downregulation promotes p53 expression. These findings demonstrate the importance of increased translation of p53 in DNA-damage responses and suggest critical roles for RPL26 and nucleolin in affecting p53 induction.
Takagi
Masatoshi
M
Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Absalon
Michael J
MJ
McLure
Kevin G
KG
Kastan
Michael B
MB
D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D012269:Ribosomal Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D000097796:Nucleolin
D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D000097796:Nucleolin; C060480:Rpl26 protein, mouse