Paul Anderson
Department of Medicine
Division of Rheumatology
Brigham and Women's Hospital
Smith 652
One Jimmy Fund Way
Boston, MA 02115
Tel: 617-525-1202
Fax: 617-525-1310
email:panderson@rics.bwh.harvard.edu
7 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. TNFa, 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 TNFa, IL-1b, COX-2 and MMP-13 transcripts, whereas TTP promotes the degradation of TNFa 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: bymonitoring the composition and function of mRNP complexes, the stress granule determines whether individual mRNAs are stored, degraded, or re-initiated.
References:
- Phillips K, Kedersha N, Shen L, Blackshear PJ, Anderson P. Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor a, cyclooxygenase 2, and inflammatory arthritis. Proc Natl Acad Sci U S A 2004;101:7:2011-6.
- Li W, Kedersha N, Chen S, Gilks N, Lee G, Anderson P. FAST is a BCL-XL-associated mitochondrial protein. Biochem Biophys Res Comm 2004;318:95-102.
- Stoecklin G, Stubbs T, Kedersha N, Blackwell TK, Anderson P. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J 2004;23:1313-24.
- Gilks N, Kedersha N, Ayodele M, Shen L, Stoecklin G, Dember LM, Anderson P. Stress granule assembly is mediated by prion-like aggregation of TIA-1. Mol Biol Cell 2004;15:5383-98.
- Li W, Simarro M, Kedersha N, Anderson P. FAST is a survival protein that senses mitochondrial stress and modulates TIA-1-regulated changes in protein expression. Mol Cell Biol 2004;24:24:10718-32.
- Kedersha N, Stoecklin G, Ayodele M, Yacono P, Lykke-Andersen J, Fitzler MJ, Scheuner D, Kaufman RJ, Golan DE, Anderson P. Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 2005;169:871-884.
Immunology webpage updated 12/02/2009