tailieunhanh - Báo cáo khoa học: Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-b1 induced murine tissue inhibitor of metalloproteinases-1 gene expression

Expression of the tissue inhibitor ofmetalloproteinases-1(Timp-1) gene can be induced by either phorbol myristate acetate (PMA) or transforming growth factorb1 (TGF-b1), 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-b1 stimulation ofTimp-1show a differential response to TSA or NaB. . | iFEBS Journal Differential effects of histone deacetylase inhibitors on phorbol ester- and TGF-p1 induced murine tissue inhibitor of metalloproteinases-1 gene expression David A. Young Olivia Billingham Clara L. Sampieri Dylan R. Edwards and Ian M. Clark Schoolof BiologicalSciences University of East Anglia Norwich UK Keywords acetylation c-Jun TGFb TIMP trichostatin A Correspondence I. M. Clark Schoolof BiologicalSciences University of East Anglia Norwich NR4 7TJ UK Tel 44 1603 592760 Fax 44 1603 592250 E-mail Present address Department of Rheumatology University of Newcastle- upon-Tyne NE2 4HH UK Received 16 November 2004 revised 12 January 2005 accepted 21 February 2005 doi Expression of the tissue inhibitor of metalloproteinases-1 Timp-1 gene can be induced by either phorbol myristate acetate PMA or transforming growth factor b1 TGF-P1 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-P1 stimulation of Timp-1 show a differential response to TSA or NaB. TSA or NaB potentiate PMA-induced Timp-1 expression but repress TGF-b1-induced Timp-1 expression. The repression of TGF-b1-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-b1-induced Timp-1 expression demonstrating that different HDACs impact on the induction of Timp-1. For either PMA or TGF-P1 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 .

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