Department of Medicine; Division of Rheumatology
Brigham and Women's Hospital, Smith 652
One Jimmy Fund Way
Boston, MA 02115
Lab Members: 2 Postdoctoral Fellows
Work in the laboratory is focused on the post-transcriptional mechanisms that regulate the production of inflammatory mediators. Many mRNAs that encode inflammatory mediators (e.g. TNFα, IL-1b, COX-2, matrix metalloproteinase) possess adenine and uridine-rich elements (AREs) in their 3' untranslated regions that inhibit translation and promote mRNA decay. The regulated activity of ARE-binding proteins (ARE-BPs) is required to overcome ARE-dependent translational repression and mRNA instability. TIA-1, TIAR and TTP are ARE-BPs that prevent the pathological overexpression of inflammatory mediators. TIA-1 and TIAR inhibit the translation of TNFα, IL-1b, COX-2 and MMP-13 transcripts, whereas TTP promotes the degradation of TNFα and COX-2 transcripts. Because of this, TIA-1 and TTP function as arthritis suppressor genes: TIA-1-/- mice develop mild arthritis, TTP-/- mice develop severe arthritis and TIA-1/TTP-/- female mice develop very severe arthritis. Whereas macrophages are a major source of arthritigenic cytokine in mice lacking TIA-1 or TTP, neutrophils are a major souce of arthritigenic cytokine in mice lacking both TIA-1 and TTP. Thus, TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritigenic cytokine.
TIA-1 and TTP also regulate the general translational arrest observed in cells subjected to environmental stress. Both TIA-1 and TTP regulate the assembly of cytoplasmic stress granules, discrete foci at which untranslated mRNAs accumulate in stressed cells. Stress-induced phosphorylation of the translation initiation factor eIF2 allows TIA-1 to promote the assembly of untranslated, non-canonical 48S preinitiation complexes that are the core constituents of stress granules. We have proposed that stress granules function as sites of mRNA triage: by monitoring the composition and function of mRNP complexes, the stress granule determines whether individual mRNAs are stored, degraded, or re-initiated.
Ohn T, Kedersha N, Hickman T, Tisdale S, Anderson P. A functional RNAi screen links O-GlcNAc modification of ribosomal proteins to stress granule and processing body assembly. Nat Cell Biol 2008 Oct;10(10):1224-31.
Yamasaki S, Ivanov P, Hu G, Anderson P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol 2009 Apr 6;185(1):35-42.
Anderson P, Kedersha N. RNA granules: post-transcriptional and epigenetic modulators of gene expression [review]. Nat Rev Mol Cell Biol 2009 June; 10(6):430-6.
Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation [review]. Nat Rev Immunol 2010 Jan 10; (1):24-35.
Emara MM, Ivanov P, Hickman T, Dawra N, Tisdale, S, Kedersha N, Guo-Fu H, Anderson P. Angiogenin-induced tiRNAs promote stress-induced stress granule assembly. J Biol Chem 2010 Apr 285:14:10959-68.
Ivanov P, Emara M, Villen J, Gygi SP, Anderson P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol Cell 2011 Aug 19; 43:613-23.
Last Update: 12/13/2012