Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction.
Impaired ribosome biogenesis is attributed to nucleolar disruption and diffusion of a subset of 60S ribosomal proteins, particularly ribosomal protein (rp)L11, into the nucleoplasm, where they inhibit MDM2, leading to p53 induction and cell-cycle arrest. Previously, we demonstrated that deletion of the 40S rpS6 gene in mouse liver prevents hepatocytes from re-entering the cell cycle after partial hepatectomy. Here, we show that this response leads to an increase in p53, which is recapitulated in culture by rpS6-siRNA treatment and rescued by the simultaneous depletion of p53. However, disruption of biogenesis of 40S ribosomes had no effect on nucleolar integrity, although p53 induction was mediated by rpL11, leading to the finding that the cell selectively upregulates the translation of mRNAs with a polypyrimidine tract at their 5'-transcriptional start site (5'-TOP mRNAs), including that encoding rpL11, on impairment of 40S ribosome biogenesis. Increased 5'-TOP mRNA translation takes place despite continued 60S ribosome biogenesis and a decrease in global translation. Thus, in proliferative human disorders involving hypomorphic mutations in 40S ribosomal proteins, specific targeting of rpL11 upregulation would spare other stress pathways that mediate the potential benefits of p53 induction.
Fumagalli
Stefano
S
Di Cara
Alessandro
A
Neb-Gulati
Arti
A
Natt
Francois
F
Schwemberger
Sandy
S
Hall
Jonathan
J
Babcock
George F
GF
Bernardi
Rosa
R
Pandolfi
Pier Paolo
PP
Thomas
George
G
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000172:deficiency / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D024363:Transcription Initiation Site; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D012333:RNA, Messenger; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C448579:ribosomal protein S6, mouse