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
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.

References:

Ivanov P, Emara M, Villen J, Gygi SP, Anderson P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol Cell 2011 Aug19;43:613-23. PMCID: PMC3160621

Simarro M, Giannattasio G, Xing W, Lundequist EM, Stewart S, Stevens RL, Orduna A, Boyce JA, Anderson P. The translational repressor T-cell intracellular antigen-1 (TIA-1) is a key modulator of th2 and th17 responses driving pulmonary inflammation induced by exposure to house dust mite. Immunol Lett 2012 Aug 30;146(1-2):8-14. PMCID: PMC3407291

Emara MM, Fujimura K, Sciaranghella D, Ivanova V, Ivanov P, Anderson P. Hydrogen peroxide induces stress granule formation independent of eIF2α phosphorylation. Biochem Biophys Res Commun 2012 Jul 13; 423(4):763-9. PMCID: PMC3399031

Fujimura K, Sasaki AT, Anderson P. Selenite targets eIF4E-binding protein-1 to inhibit translation initiation and induce the assembly of non-canonical stress granules. Nucleic Acids Res 2012 Sep 1;40(16):8099-110. PMCID: PMC3439927

Lei W, Ivanov P, Anderson P. Fas-activated Ser/Thr phosphoprotein (FAST) is a eukaryotic initiation factor 4E-binding protein that regulates mRNA stability and cell survival. Translation 2013;1:1:e24047.

Ivanov P, Anderson P. Post-transcriptional regulatory networks in immunity. Immunol Rev 2013 May; 253(1):253-72. PMID: 23550651 [PubMed - in process]



Last Update: 1/6/2014