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PMID: 18042545 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S.

p38alpha stabilizes interleukin-6 mRNA via multiple AU-rich elements.

The Journal of biological chemistry ·Vol. 283 ·No. 4 ·2008-01-25 ·Pages 1778-85

Zhao W, Liu M, Kirkwood KL

Abstract

AU-rich elements (AREs) in the 3'-untranslated region (UTR) of unstable mRNA dictate their degradation or mediate translational repression. Cell signaling through p38alpha MAPK is necessary for post-transcriptional regulation of many pro-inflammatory cytokines. Here, the cis-acting elements of interleukin-6 (IL-6) 3'-UTR mRNA that required p38alpha signaling for mRNA stability and translation were identified. Using mouse embryonic fibroblasts (MEFs) derived from p38alpha(+/+) and p38alpha(-/-) mice, we observed that p38alpha is obligatory for the IL-1-induced IL-6 biosynthesis. IL-6 mRNA stability is promoted by p38alpha via 3'-UTR. To understand the mechanism of cis-elements regulated by p38alpha at post-transcriptional level, truncation of 3'-UTR and the full-length 3'-UTR with individual AUUUA motif mutation placed in gene reporter system was employed. Mutation-based screen performed in p38alpha(+/+) and p38alpha(-/-) mouse embryonic fibroblast cells revealed that ARE1, ARE2, and ARE5 in IL-6 3'-UTR were targeted by p38alpha, and truncation-based screen showed that IL-6 3'-UTR-(56-173) was targeted by p38alpha to stable mRNA. RNA secondary structure analysis indicated that modulated reporter gene expression was consistent with predicted secondary structure changes.

MeSH Terms
3' Untranslated Regions/genetics,metabolism Animals Cells, Cultured Embryo, Mammalian/cytology,enzymology Fibroblasts/cytology,enzymology Interleukin-1/pharmacology Interleukin-6/biosynthesis,genetics MAP Kinase Signaling System/drug effects,physiology Mice Mice, Knockout Mitogen-Activated Protein Kinase 14/metabolism Nucleic Acid Conformation RNA Processing, Post-Transcriptional/drug effects,physiology RNA Stability/drug effects,physiology
Chemicals
3' Untranslated Regions Interleukin-1 Interleukin-6 Mitogen-Activated Protein Kinase 14
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Zhao Wenpu
Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, Michigan 48109-1078, USA.
Liu Min
Kirkwood Keith L
References (43)
43 references, click to expand
  1. RNA-protein interactions in the control of stability and localization of messenger RNA (review).
    Int J Mol Med. 2000 Feb;5(2):111-23 PMID: 10639588
  2. HuR and mRNA stability.
    Cell Mol Life Sci. 2001 Feb;58(2):266-77 PMID: 11289308
  3. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin.
    Science. 1998 Aug 14;281(5379):1001-5 PMID: 9703499
  4. p38 MAPK regulates IL-1beta induced IL-6 expression through mRNA stability in osteoblasts.
    Immunol Invest. 2004 May;33(2):213-33 PMID: 15195698
  5. Interleukin-6: from basic science to medicine--40 years in immunology.
    Annu Rev Immunol. 2005;23:1-21 PMID: 15771564
  6. A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer.
    Genes Dev. 1997 Apr 15;11(8):1023-36 PMID: 9136930
  7. Regulation of interleukin-1beta-induced interleukin-6 gene expression in human fibroblast-like synoviocytes by p38 mitogen-activated protein kinase.
    J Biol Chem. 1998 Sep 18;273(38):24832-8 PMID: 9733787
  8. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis.
    Nature. 1994 Dec 22-29;372(6508):739-46 PMID: 7997261
  9. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas.
    Nature. 1988 Mar 3;332(6159):83-5 PMID: 3258060
  10. Effect of interleukin-6 on the growth of human lung cancer cell line.
    Chin Med J (Engl). 1998 Mar;111(3):265-8 PMID: 10374431
  11. Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells.
    J Exp Med. 2000 Mar 6;191(5):859-70 PMID: 10704466
  12. Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional gene expression.
    Am J Hum Genet. 1997 Aug;61(2):273-8 PMID: 9311730
  13. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis.
    Eur J Immunol. 1988 Nov;18(11):1797-801 PMID: 2462501
  14. mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure.
    Chembiochem. 2004 Oct 4;5(10):1432-47 PMID: 15457527
  15. p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level.
    Biochem Biophys Res Commun. 1997 Jan 3;230(1):44-8 PMID: 9020057
  16. Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs.
    EMBO J. 2004 Aug 4;23(15):3092-102 PMID: 15257295
  17. Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1.
    Mol Cell Biol. 1993 Dec;13(12):7652-65 PMID: 8246982
  18. Identification of TIAR as a protein binding to the translational regulatory AU-rich element of tumor necrosis factor alpha mRNA.
    J Biol Chem. 1999 Jan 22;274(4):2322-6 PMID: 9890998
  19. Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro.
    Cancer Res. 1997 Jan 1;57(1):141-6 PMID: 8988055
  20. MRNA stability and the control of gene expression: implications for human disease.
    Neurochem Res. 2002 Oct;27(10):957-80 PMID: 12462398
  21. Cellular mutants define a common mRNA degradation pathway targeting cytokine AU-rich elements.
    RNA. 2001 Nov;7(11):1578-88 PMID: 11720287
  22. The effect of RNA secondary structures on RNA-ligand binding and the modifier RNA mechanism: a quantitative model.
    Gene. 2005 Jan 17;345(1):3-12 PMID: 15716109
  23. Post-transcriptional regulation of gene expression by degradation of messenger RNAs.
    J Cell Physiol. 2003 Jun;195(3):356-72 PMID: 12704645
  24. Computer prediction of RNA structure.
    Methods Enzymol. 1989;180:262-88 PMID: 2482418
  25. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element.
    Genes Dev. 1999 Jul 15;13(14):1884-97 PMID: 10421639
  26. Functional cloning of BRF1, a regulator of ARE-dependent mRNA turnover.
    EMBO J. 2002 Sep 2;21(17):4709-18 PMID: 12198173
  27. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta).
    J Biol Chem. 1996 Jul 26;271(30):17920-6 PMID: 8663524
  28. Post-transcriptional regulation of pro-inflammatory gene expression.
    Arthritis Res. 2000;2(3):172-4 PMID: 11094425
  29. Involvement of microRNA in AU-rich element-mediated mRNA instability.
    Cell. 2005 Mar 11;120(5):623-34 PMID: 15766526
  30. AU-rich element-mediated translational control: complexity and multiple activities of trans-activating factors.
    Biochem Soc Trans. 2002 Nov;30(Pt 6):952-8 PMID: 12440953
  31. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3.
    Nat Immunol. 2004 Jan;5(1):98-103 PMID: 14661019
  32. Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene.
    Mol Cell Biol. 1990 Jun;10(6):2757-64 PMID: 2111442
  33. Activation and signaling of the p38 MAP kinase pathway.
    Cell Res. 2005 Jan;15(1):11-8 PMID: 15686620
  34. p38 mitogen-activated protein kinase inhibitors--mechanisms and therapeutic potentials.
    Pharmacol Ther. 1999 May-Jun;82(2-3):389-97 PMID: 10454214
  35. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels.
    J Biol Chem. 2002 Feb 1;277(5):3065-8 PMID: 11741878
  36. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase.
    J Biol Chem. 1997 Sep 19;272(38):23668-74 PMID: 9295308
  37. The p38 signal transduction pathway: activation and function.
    Cell Signal. 2000 Jan;12(1):1-13 PMID: 10676842
  38. Post-transcriptional regulation of RNase-L expression is mediated by the 3'-untranslated region of its mRNA.
    J Biol Chem. 2007 Mar 16;282(11):7950-60 PMID: 17237228
  39. Using RNA secondary structures to guide sequence motif finding towards single-stranded regions.
    Nucleic Acids Res. 2006;34(17):e117 PMID: 16987907
  40. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis.
    Nat Cell Biol. 1999 Jun;1(2):94-7 PMID: 10559880
  41. Autocrine growth promotion by multiple hematopoietic growth factors in the established renal cell carcinoma line KU-19-20.
    Cell Tissue Res. 2000 Sep;301(3):353-67 PMID: 10994781
  42. Messenger-RNA-binding proteins and the messages they carry.
    Nat Rev Mol Cell Biol. 2002 Mar;3(3):195-205 PMID: 11994740
  43. Regulation of expression of interleukin-6. Molecular and clinical studies.
    Ann N Y Acad Sci. 1989;557:353-61; discussion 361-2 PMID: 2786700
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M707573200
Published
2008-01-25
Epub
2007-00-27
Pages
1778-85
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2806577
Subset
IM
Grants
NIDCR NIH HHS · R01 DE018290 · United States
NIDCR NIH HHS · R01 DE018290-01 · United States
External Links
PubMed source DOI: 10.1074/jbc.M707573200 PMC Full Text View journal details
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