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

David A. Young, Olivia Billingham, Clara L. Sampieri, Dylan R. Edwards, Ian M. Clark

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28 Citations (Scopus)


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 Sp1 binding motif.
Original languageEnglish
Pages (from-to)1912-1926
Number of pages15
JournalFEBS Journal
Issue number8
Publication statusPublished - 2005

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