mTOR signaling regulates the processing of pre-rRNA in human cells.

School of Biological Sciences, University of Southampton, SO17 1BJ, UK.
Nucleic Acids Research (Impact Factor: 8.81). 11/2011; 40(6):2527-39. DOI: 10.1093/nar/gkr1040
Source: PubMed

ABSTRACT Signaling through the mammalian target of rapamycin, complex 1 (mTORC1), positively regulates the transcription of ribosomal RNA (rRNA) and the synthesis of ribosomal proteins, thereby promoting the complex process of ribosome biogenesis. The major rRNAs are transcribed as a single precursor, which must be processed to create the 5.8S, 18S and 28S rRNAs. We used a new non-radioactive labeling approach to study the effects of rapamycin, an inhibitor of mTORC1, on rRNA synthesis. Rapamycin not only impaired synthesis of new 18S, 28S or 5S rRNA but also induced their decay. This prompted us to examine the effects of rapamycin on rRNA processing. We show that rapamycin also interferes with the processing events that generate 18S and 28S rRNA. rRNA transcription and processing occur in regions of the nucleus known as nucleoli. We find that the mTORC1 components raptor and mTOR are both present in nucleoli, where they may regulate rRNA maturation events. While rapamycin has no effect on overall nucleolar morphology or its proteome, it does induce loss of mTOR and raptor from them. These data show that mTORC1 is located in nucleoli where it acts to regulate events involved in ribosome biogenesis including the maturation of rRNA molecules.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Ribosome biogenesis is critical for cells to generate the ribosomes they need for protein synthesis in order to to survive, grow and proliferate. It is a complex process, involving the coordinated production of four different RNA species and about 80 proteins, as well as their assembly into functional ribosomal subunits. Given its high demand for amino acids and nucleotides, it is also a metabolically expensive process for the cell. The mammalian target of rapamycin complex 1 (mTORC1) is a protein kinases which is activated by nutrients, anabolic hormones and oncogenic signaling pathways. mTORC1 positively regulates several steps in ribosome biogenesis, including ribosomal RNA transcription, the synthesis of ribosomal proteins and other components required for ribosome assembly. mTORC1 can thus coordinate stimuli which promote ribosome production with the various steps involved in this process. Although important advances have been made in our understanding of mTORC1 signaling, major questions remain about the molecular mechanisms by which it regulates ribosome biogenesis.
    Seminars in Cell and Developmental Biology 08/2014; DOI:10.1016/j.semcdb.2014.08.004 · 5.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The proteome of cells is synthesized by ribosomes, complex ribonucleoproteins that in eukaryotes contain 79-80 proteins and four ribosomal RNAs (rRNAs) more than 5,400 nucleotides long. How these molecules assemble together and how their assembly is regulated in concert with the growth and proliferation of cells remain important unanswered questions. Here, we review recently emerging principles to understand how eukaryotic ribosomal proteins drive ribosome assembly in vivo. Most ribosomal proteins assemble with rRNA cotranscriptionally; their association with nascent particles is strengthened as assembly proceeds. Each subunit is assembled hierarchically by sequential stabilization of their subdomains. The active sites of both subunits are constructed last, perhaps to prevent premature engagement of immature ribosomes with active subunits. Late-assembly intermediates undergo quality-control checks for proper function. Mutations in ribosomal proteins that affect mostly late steps lead to ribosomopathies, diseases that include a spectrum of cell type-specific disorders that often transition from hypoproliferative to hyperproliferative growth. Expected final online publication date for the Annual Review of Biochemistry Volume 84 is June 02, 2015. Please see for revised estimates.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nucleoli and cytoplasmic stress granules (SGs) are subcellular compartments that modulate the response to endogenous and environmental signals to control cell survival. In our opinion, nucleoli and SGs are functionally linked; they are distant relatives that combine forces when cellular homeostasis is threatened. Several lines of evidence support this idea; nucleoli and SGs share molecular building blocks, they are regulated by common signaling pathways, and communicate when vital cellular functions become compromised. Together, nucleoli and SGs orchestrate physiological responses that are directly relevant to stress and human health. As both compartments have established roles in neurodegenerative diseases, cancer and virus infections, we propose that these conditions will benefit from therapeutic interventions that target simultaneously nucleoli and SGs.
    Traffic 06/2014; DOI:10.1111/tra.12191 · 4.71 Impact Factor

Full-text (3 Sources)

Available from
May 21, 2014