The p38 MAPK regulates IL-24 expression by stabilization of the 3' UTR of IL-24 mRNA
| Autor: | Tue Wenzel Kragstrup, Kristian Otkjaer, Søren R. Paludan, Helmut Holtmann, Matthias Gaestel, Claus Johansen, Knud Kragballe, Lars Iversen |
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| Rok vydání: | 2009 |
| Předmět: |
MAPK/ERK pathway
Untranslated region Dermatology/Psoriasis and Other Inflammatory Diseases Pyridines Interleukin-1beta lcsh:Medicine Immunology/Autoimmunity Biology p38 Mitogen-Activated Protein Kinases Cell Biology/Cell Signaling Cell Line Dermatology/Skin Cancers including Melanoma and Lymphoma chemistry.chemical_compound Immunology/Leukocyte Signaling and Gene Expression Gene expression Humans RNA Messenger lcsh:Science Protein kinase A 3' Untranslated Regions Protein Kinase Inhibitors Anisomycin Cell Biology/Gene Expression Messenger RNA Multidisciplinary Three prime untranslated region Interleukins lcsh:R Imidazoles MRNA stabilization Molecular biology Cell biology Enzyme Activation chemistry Oncology lcsh:Q Molecular Biology/mRNA Stability Research Article |
| Zdroj: | PLoS ONE Otkjaer, K, Holtmann, H, Kragstrup, T W, Paludan, S R, Johansen, C, Gaestel, M, Kragballe, K & Iversen, L 2010, ' The p38 MAPK regulates IL-24 expression by stabilization of the 3' UTR of IL-24 mRNA ', P L o S One, vol. 5, no. 1, pp. e8671 . https://doi.org/10.1371/journal.pone.0008671 PLoS ONE, Vol 5, Iss 1, p e8671 (2010) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0008671 |
| Popis: | Udgivelsesdato: 2010-null BACKGROUND: IL-24 (melanoma differentiation-associated gene-7 (mda-7)), a member of the IL-10 cytokine family, possesses the properties of a classical cytokine as well as tumor suppressor effects. The exact role of IL-24 in the immune system has not been defined but studies have indicated a role for IL-24 in inflammatory conditions such as psoriasis. The tumor suppressor effects of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis. Current knowledge on the regulation of IL-24 expression is sparse. Previous studies have suggested that mRNA stabilization is of major importance to IL-24 expression. Yet, the mechanisms responsible for the regulation of IL-24 mRNA stability remain unidentified. As p38 MAPK is known to regulate gene expression by interfering with mRNA degradation we examined the role of p38 MAPK in the regulation of IL-24 gene expression in cultured normal human keratinocytes. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we show that anisomycin- and IL-1beta- induced IL-24 expression is strongly dependent on p38 MAPK activation. Studies of IL-24 mRNA stability in anisomycin-treated keratinocytes reveal that the p38 MAPK inhibitor SB 202190 accelerates IL-24 mRNA decay suggesting p38 MAPK to regulate IL-24 expression by mRNA-stabilizing mechanisms. The insertion of the 3' untranslated region (UTR) of IL-24 mRNA in a tet-off reporter construct induces degradation of the reporter mRNA. The observed mRNA degradation is markedly reduced when a constitutively active mutant of MAPK kinase 6 (MKK6), which selectively activates p38 MAPK, is co-expressed. CONCLUSIONS/SIGNIFICANCE: Taken together, we here report p38 MAPK as a regulator of IL-24 expression and determine interference with destabilization mediated by the 3' UTR of IL-24 mRNA as mode of action. As discussed in the present work these findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine. |
| Databáze: | OpenAIRE |
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