An adenine and uridine-rich element (ARE) located in the 3' untranslated region of TNF a transcripts regulates mRNA stability and translation in a way that prevents the overexpression of TNFa. ARE-dependent post-transcriptional control requires the activity of RNA-binding proteins that function as translational repressors (e.g. TIA-l and TIAR), rnRNA stabilizers (e.g. HuR) and mRNA destabilizers (e.g. AUF1 and TTP). Surprisingly little is known about how these ARE-binding proteins (ARE-BPs) interact to regulate the expression of TNFa. TIA-l (and/or TIAR) promote the general translational repression that accompanies environmental stress and the selective translational repression of TNFa that occurs in LPS-activated macrophages. Translationally repressed transcripts transiently accumulate at discrete cytoplasmic foci known as stress granules (SGs). We hypothesize that the SG functions as a translational checkpoint that determines whether TNFa transcripts are translated or degraded. We further propose that this decision is influenced by ARE-BPs that regulate transcript stability (e.g. HuR, AUF1 and TTP). We will test these hypotheses by determining: i) the effect of a TIA-l truncation mutant that inhibits the assembly of SGs on the production of TNFa, ii) the mRNA and protein composition of LPS-induced SGs in macrophages, iii) whether different functional classes of ARE-BPs bind to the TNFa ARE in a cooperative, non-cooperative or competitive manner, and iv) how different functional classes of ARE-Bps cooperate to regulate the production of TNFa. Completion of these aims will improve our understanding of how ARE-BPs interact to regulate the production of TNFa. These studies might also identify molecular targets for the development of orally available TNFa blockers that can be used to treat patients with rheumatoid arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050167-05
Application #
6890895
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Johnson, David R
Project Start
2001-09-30
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2007-05-31
Support Year
5
Fiscal Year
2005
Total Cost
$325,100
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Stoecklin, Georg; Tenenbaum, Scott A; Mayo, Thomas et al. (2008) Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J Biol Chem 283:11689-99
Stoecklin, Georg; Anderson, Paul (2007) In a tight spot: ARE-mRNAs at processing bodies. Genes Dev 21:627-31
Simarro, Maria; Mauger, David; Rhee, Kirsten et al. (2007) Fas-activated serine/threonine phosphoprotein (FAST) is a regulator of alternative splicing. Proc Natl Acad Sci U S A 104:11370-5
Anderson, Paul; Kedersha, Nancy (2006) RNA granules. J Cell Biol 172:803-8
Stoecklin, Georg; Anderson, Paul (2006) Posttranscriptional mechanisms regulating the inflammatory response. Adv Immunol 89:1-37
Stoecklin, Georg; Mayo, Thomas; Anderson, Paul (2006) ARE-mRNA degradation requires the 5'-3' decay pathway. EMBO Rep 7:72-7
McInerney, Gerald M; Kedersha, Nancy L; Kaufman, Randal J et al. (2005) Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation. Mol Biol Cell 16:3753-63
Wax, Stephen D; Nakamura, Hideki; Anderson, Paul J (2005) The tumor necrosis factor-alpha AU-rich element inhibits the stable association of the 40S ribosomal subunit with RNA transcripts. Biochem Biophys Res Commun 333:1100-6
Kedersha, Nancy; Stoecklin, Georg; Ayodele, Maranatha et al. (2005) Stress granules and processing bodies are dynamically linked sites of mRNP remodeling. J Cell Biol 169:871-84

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