| Stress granules: sites of mRNA triage that regulate mRNA stability and translatability. | |
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MedLine Citation:
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PMID: 12440955 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mammalian stress granules (SGs) are cytoplasmic domains into which mRNAs are sorted dynamically in response to phosphorylation of eukaryotic initiation factor (eIF) 2alpha, a key regulatory step in translational initiation. The activation of one or more of the eIF2alpha kinases leads to SG assembly by decreasing the levels of eIF2-GTP-tRNA(Met), the ternary complex that is normally required for loading the initiator methionine onto the 48 S preinitiation complex to begin translation. This stress-induced scarcity of eIF2-GTP-tRNA(Met) allows the RNA-binding proteins TIA-1 (T-cell internal antigen-1) and TIAR (TIA-1-related protein) to bind the 48 S complex in lieu of the ternary complex, thereby promoting polysome disassembly and the concurrent routing of the mRNA into a SG. The actual formation of SGs occurs upon auto-aggregation of the prion-like C-termini of TIA-1 proteins; this aggregation is reversed in vivo by overexpression of the heat-shock protein (HSP) chaperone HSP70. Remarkably, HSP70 mRNA is excluded from SGs and is preferentially translated during stress, indicating that the RNA composition of the SG is selective. Moreover, the effects of HSP70 on TIA aggregation suggest a feedback loop whereby HSP70 synthesis is auto-regulated. Proteins that promote mRNA stability [e.g. HuR (Hu protein R)] and destabilize mRNA [i.e. tristetraprolin (TTP)] are also recruited to SGs, suggesting that SGs effect a process of mRNA triage, by promoting polysome disassembly and routing mRNAs to cytoplasmic domains enriched for HuR and TTP. This model reveals connections between the eIF2alpha kinase system, mRNA stability and cellular chaperone levels. |
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Authors:
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N Kedersha; P Anderson |
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Publication Detail:
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Type: Journal Article; Review |
Journal Detail:
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Title: Biochemical Society transactions Volume: 30 ISSN: 0300-5127 ISO Abbreviation: Biochem. Soc. Trans. Publication Date: 2002 Nov |
Date Detail:
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Created Date: 2002-11-20 Completed Date: 2003-06-10 Revised Date: 2005-11-16 |
Medline Journal Info:
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Nlm Unique ID: 7506897 Medline TA: Biochem Soc Trans Country: England |
Other Details:
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Languages: eng Pagination: 963-9 Citation Subset: IM |
Affiliation:
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Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith 652, 1 Jimmy Fund Way, Boston, MA 02115, USA. nkedersha@rics.bwh.harvard.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line Cytoplasmic Granules / metabolism* Humans Microscopy, Fluorescence Models, Biological Molecular Chaperones Prions / metabolism Protein Biosynthesis* Protein Structure, Tertiary RNA Stability RNA, Messenger / chemistry*, metabolism* Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Molecular Chaperones; 0/Prions; 0/RNA, Messenger |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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