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Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-β1 induced murine tissue inhibitor of metalloproteinases-1 gene expression

Lookup NU author(s): Professor David YoungORCiD


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Expression of the tissue inhibitor of metalloproteinases-1 (Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factor β1 (TGF-β1), although the signalling pathways involved are not clearly defined. Canonically, histone deacetylase inhibitors (HDACi) such as trichostatin A (TSA) or sodium butyrate (NaB) increase total cellular histone acetylation and activate expression of susceptible genes. Remarkably, PMA and TGF-β1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-β1-induced Timp-1 expression. The repression of TGF-β1-induced Timp-1 by TSA was maximal at 5 ng·mL-1, while for the superinduction of PMA-induced Timp-1 expression, the maximal dose is > 500 ng·mL-1 TSA. A further HDACi, valproic acid, did not block TGF-β1-induced Timp-1 expression, demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-β1 to induce Timp-1 expression, new protein synthesis is required, and the induction of AP-1 factors closely precedes that of Timp-1. The effects of the HDACi can be reiterated in transient transfection using Timp-1 promoter constructs. Mutation or deletion of the AP-1 motif (-59/-53) in the Timp-1 promoter diminishes PMA-induction of reporter constructs, however, the further addition of TSA still superinduces the reporter. In c-Jun-/- cells, PMA still stimulates Timp-1 expression, but TSA superinduction is lost. Transfection of a series of Timp-1 promoter constructs identified three regions through which TSA superinduces PMA-induced Timp-1 and we have demonstrated specific protein binding to two of these regions which contain either an avian erythroblastosis virus E26 (v-ets) oncogene homologue (Ets) or Spl binding motif. © 2005 FEBS.

Publication metadata

Author(s): Young DA, Billingham O, Sampieri CL, Edwards DR, Clark IM

Publication type: Article

Publication status: Published

Journal: FEBS Journal

Year: 2005

Volume: 272

Issue: 8

Pages: 1912-1926

Print publication date: 01/04/2005

ISSN (print): 1742-464X

ISSN (electronic): 1742-4658

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/j.1742-4658.2005.04622.x

PubMed id: 15819885


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