Abbreviated Journal Title

J. Biol. Chem.

Keywords

Zinc-Finger Proteins; Messenger-Rna; Macrophage Activation; Inflammatory; Diseases; Gene-Expression; Tnf-Alpha; Family; Pathway; Localization; Transduction; Biochemistry & Molecular Biology

Abstract

Tristetraprolin (TTP) is a CCCH zinc finger-containing protein that destabilizes mRNA by binding to an AU-rich element. Mice deficient in TTP develop a severe inflammatory syndrome mainly because of overproduction of tumor necrosis factor alpha. We report here that TTP also negatively regulates NF-kappa B signaling at the transcriptional corepressor level, by which it may repress inflammatory gene transcription. TTP expression inhibited NF-kappa B-dependent transcription. However, overexpression of TTP did not affect reporter mRNA stability. Instead, TTP functioned as a corepressor of p65/NF-kappa B. In support of this concept, we found that TTP physically interacted with the p65 subunit of NF-kappa B and was also associated with HDAC1, -3, and -7 in vivo. Treatment with histone deacetylase inhibitors or small interfering RNA induced HDAC1 or HDAC3 knockdown completely or partly abolished the inhibitory activity of TTP on NF-kappa B reporter activation. Consistently, chromatin immuno-precipitation showed decreased recruitment of HDAC1 and increased recruitment of CREB-binding protein on the Mcp-1 promoter in TTP(-/-) cells compared with wild-type cells. Moreover, overexpression of TTP blocked CREB-binding protein-induced acetylation of p65/NF-kappa B. Taken together, these data suggest that TTP may also function in vivo as a modulator in suppressing the transcriptional activity of NF-kappa B.

Journal Title

Journal of Biological Chemistry

Volume

284

Issue/Number

43

Publication Date

1-1-2009

Document Type

Article

Language

English

First Page

29383

Last Page

29390

WOS Identifier

WOS:000270896800019

ISSN

0021-9258

Download

Share

COinS