Absence of nucleolar disruption after impairment of 40S ribosome biogenesis reveals an rpL11-translation-dependent mechanism of p53 induction
Stefano Fumagalli,Alessandro Di Cara,Arti Neb-Gulati,Francois Natt,Sandy Schwemberger,Jonathan Hall,George F. Babcock,George F. Babcock,Rosa Bernardi,Pier Paolo Pandolfi,George Thomas +10 more
TLDR
The finding that the cell selectively upregulates the translation of mRNAs with a polypyrimidine tract at their 5′-transcriptional start site, including that encoding rpL11, on impairment of 40S ribosome biogenesis, would spare other stress pathways that mediate the potential benefits of p53 induction.Abstract:
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 inductionread more
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Journal ArticleDOI
The Nucleolus under Stress
TL;DR: Nucleolar function in the stress-induced regulation of p53 and the specific changes in nucleolar morphology and composition that occur upon stress are reviewed.
Journal ArticleDOI
Ribosomopathies: human disorders of ribosome dysfunction.
TL;DR: The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies.
Journal ArticleDOI
Signaling to p53: ribosomal proteins find their way.
Yanping Zhang,Hua Lu +1 more
TL;DR: The ribosomal protein-MDM2-p53 signaling pathway provides a molecular switch that may constitute a surveillance network monitoring the integrity of Ribosomal biogenesis.
Journal ArticleDOI
Ribosomal proteins: functions beyond the ribosome
TL;DR: The current understanding of how ribosomal stress provokes the accumulation of ribosome-free Ribosomal proteins, as well as the ribosomesome-independent functions of ribOSomal proteins in tumorigenesis, immune signaling, and development are overviewed.
Journal ArticleDOI
Inhibition of MDM2-mediated p53 ubiquitination and degradation by ribosomal protein L5. Vol. 279 (2004) 44475–44482
Mu-Shui Dai,Hua Lu +1 more
TL;DR: It is proposed that the MDM 2-L5-L11-L23 complex functions to inhibit MDM2-mediated p53 ubiquitination and thus activates p53.
References
More filters
Journal ArticleDOI
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
TL;DR: A new method of total RNA isolation by a single extraction with an acid guanidinium thiocyanate-phenol-chloroform mixture is described, providing a pure preparation of undegraded RNA in high yield and can be completed within 4 h.
Journal ArticleDOI
Exploration, normalization, and summaries of high density oligonucleotide array probe level data
Rafael A. Irizarry,Bridget G. Hobbs,Francois Collin,Yasmin Beazer-Barclay,Kristen J. Antonellis,Uwe Scherf,Terence P. Speed +6 more
TL;DR: There is no obvious downside to using RMA and attaching a standard error (SE) to this quantity using a linear model which removes probe-specific affinities, and the exploratory data analyses of the probe level data motivate a new summary measure that is a robust multi-array average (RMA) of background-adjusted, normalized, and log-transformed PM values.
Journal ArticleDOI
p53 in health and disease.
Karen H. Vousden,David P. Lane +1 more
TL;DR: It is now becoming clear that p53 can have a much broader role and can contribute to the development, life expectancy and overall fitness of an organism.
Book
Translational control of gene expression
TL;DR: Origins and Principles of Translational Control, Genetic Approaches to Translation Initiation in Saccharomyces cerevisiae, and Programmed translational Frameshifting, Hopping, an
Journal ArticleDOI
Rapamycin suppresses 5′TOP mRNA translation through inhibition of p70s6k
Harold B.J. Jefferies,Stefano Fumagalli,Patrick B. Dennis,Christoph Reinhard,Richard B. Pearson,George Thomas +5 more
TL;DR: It is demonstrated that an intact polypyrimidine tract is required for rapamycin to elicit an inhibitory effect on the translation of mRNAs encoding ribosomal proteins and elongation factors.