TY - JOUR
T1 - Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translationdependent mechanism of p53 induction
AU - Fumagalli, Stefano
AU - Di Cara, Alessandro
AU - Neb-Gulati, Arti
AU - Natt, Francois
AU - Schwemberger, Sandy
AU - Hall, Jonathan
AU - Babcock, George F.
AU - Bernardi, Rosa
AU - Pandolfi, Pier Paolo
AU - Thomas, George
PY - 2009
Y1 - 2009
N2 - 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 cellcycle arrest1-4. Previously, we demonstrated that deletion of the 40S rpS6 gene in mouse liver prevents hepatocytes from re-entering the cell cycle after partial hepatectomy5. 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 proteins6,7, specific targeting of rpL11 upregulation would spare other stress pathways that mediate the potential benefits of p53 induction8.
AB - 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 cellcycle arrest1-4. Previously, we demonstrated that deletion of the 40S rpS6 gene in mouse liver prevents hepatocytes from re-entering the cell cycle after partial hepatectomy5. 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 proteins6,7, specific targeting of rpL11 upregulation would spare other stress pathways that mediate the potential benefits of p53 induction8.
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U2 - 10.1038/ncb1858
DO - 10.1038/ncb1858
M3 - Article
C2 - 19287375
AN - SCOPUS:64049107857
VL - 11
SP - 501
EP - 508
JO - Nature Cell Biology
JF - Nature Cell Biology
SN - 1465-7392
IS - 4
ER -