DF/HCC Program Affiliation

Cancer Immunology

Research Abstract

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 constitutive 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, 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 source of arthritienic 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 eIF2a 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.

Publications

• Stoecklin G, Anderson P.Posttranscriptional mechanisms regulating the inflammatory response.Adv Immunol 2006;89:1-37.
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• Anderson P, Kedersha N.RNA granules.J Cell Biol 2006 Mar 13;172(6):803-8.
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• 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 Jun 20;169(6):871-84.
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