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The Mnks are novel components in the control of TNF? biosynthesis and phosphorylate and regulate hnRNP A1

The Mnks are novel components in the control of TNF? biosynthesis and phosphorylate and regulate hnRNP A1
The Mnks are novel components in the control of TNF? biosynthesis and phosphorylate and regulate hnRNP A1
Posttranscriptional regulatory mechanisms control TNF alpha expression through AU-rich elements in the 3'UTR of its mRNA. This is mediated through Erk and p38 MAP kinase signaling, although the mechanisms involved remain poorly understood. Here, we show that the MAP kinase signal-integrating kinases (Mnks), which are activated by both these pathways, regulate TNFa expression in T cells via the 3'UTR. A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNFa production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNFa 3'UTR. We identify ARE binding proteins that are Mnk substrates, such as hnRNP A1, which they phosphorylate at two sites in vitro. hnRNP A1 is phosphorylated in response to T cell activation, and this is blocked by Mnk inhibition. Moreover, Mnk-mediated phosphorylation decreases binding of hnRNP A1 to TNF alpha-ARE in vitro or TNF alpha-mRNA in vivo. Therefore, Mnks are novel players in cytokine regulation and potential new targets for antiinflammatory therapy.
tumor necrosis factor, activated protein-kinase, initiation-factor 4E, AU -rich elements, p38 map kinase, messenger-rna, in-vivo, binding protein, gene expression, T lymphocytes
1097-4180
177-189
Buxade, M.
3929371b-f21d-4fb2-8d65-c8086ef44311
Parra, J.L.
f11649c3-e751-4c2c-b91b-a3567638098f
Rousseau, S.
bd75a670-9734-48d0-94c6-4cfd3ddbb5d8
Shpiro, N.
70eeb609-1a3e-46f0-b659-564a6f8dbb0d
Marquez, R.
4d361708-bd52-4cc7-a642-d75d34feba80
Morrice, N.
b8752648-b08e-48d1-99d4-7abb083299e2
Bain, J.
a12c0664-642a-458d-acc8-c4c2d76ceb57
Espel, E.
2819eb1d-67c1-4748-9683-f3a96dee3c59
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e
Buxade, M.
3929371b-f21d-4fb2-8d65-c8086ef44311
Parra, J.L.
f11649c3-e751-4c2c-b91b-a3567638098f
Rousseau, S.
bd75a670-9734-48d0-94c6-4cfd3ddbb5d8
Shpiro, N.
70eeb609-1a3e-46f0-b659-564a6f8dbb0d
Marquez, R.
4d361708-bd52-4cc7-a642-d75d34feba80
Morrice, N.
b8752648-b08e-48d1-99d4-7abb083299e2
Bain, J.
a12c0664-642a-458d-acc8-c4c2d76ceb57
Espel, E.
2819eb1d-67c1-4748-9683-f3a96dee3c59
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e

Buxade, M., Parra, J.L., Rousseau, S., Shpiro, N., Marquez, R., Morrice, N., Bain, J., Espel, E. and Proud, C.G. (2005) The Mnks are novel components in the control of TNF? biosynthesis and phosphorylate and regulate hnRNP A1. Immunity, 23 (2), 177-189. (doi:10.1016/j.immuni.2005.06.009).

Record type: Article

Abstract

Posttranscriptional regulatory mechanisms control TNF alpha expression through AU-rich elements in the 3'UTR of its mRNA. This is mediated through Erk and p38 MAP kinase signaling, although the mechanisms involved remain poorly understood. Here, we show that the MAP kinase signal-integrating kinases (Mnks), which are activated by both these pathways, regulate TNFa expression in T cells via the 3'UTR. A selective Mnk inhibitor or siRNA-mediated knockdown of Mnk1 inhibits TNFa production in T cells, whereas Mnk1 overexpression enhances expression of a reporter construct containing the TNFa 3'UTR. We identify ARE binding proteins that are Mnk substrates, such as hnRNP A1, which they phosphorylate at two sites in vitro. hnRNP A1 is phosphorylated in response to T cell activation, and this is blocked by Mnk inhibition. Moreover, Mnk-mediated phosphorylation decreases binding of hnRNP A1 to TNF alpha-ARE in vitro or TNF alpha-mRNA in vivo. Therefore, Mnks are novel players in cytokine regulation and potential new targets for antiinflammatory therapy.

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More information

Submitted date: 17 December 2004
Published date: 23 August 2005
Keywords: tumor necrosis factor, activated protein-kinase, initiation-factor 4E, AU -rich elements, p38 map kinase, messenger-rna, in-vivo, binding protein, gene expression, T lymphocytes

Identifiers

Local EPrints ID: 48774
URI: https://eprints.soton.ac.uk/id/eprint/48774
ISSN: 1097-4180
PURE UUID: 0feaf9f1-3696-4397-91f1-cd2a7f1be2e2

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Date deposited: 12 Oct 2007
Last modified: 17 Jul 2017 14:58

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