Date of Award
Campus Access Dissertation
Rekha C Patel
Matrix metalloproteinase-9 (MMP-9) is a 92 kDa zinc-dependant endopeptidase that degrades components of the extracellular matrix. Enhanced expression of MMP-9 has been implicated in many pathological conditions including cancer metastasis, multiple sclerosis, and atherosclerosis. Although it has been widely noted that interferon-beta; (IFN-beta) downregulates both the basal and phorbol 12-myristate 13-acetate (PMA)-induced MMP-9 expression at the transcriptional level, the molecular mechanism of this repression is poorly understood. We describe here a novel mechanism for repression of MMP-9 transcription by IFN-beta in HT1080 fibrosarcoma cells. Using reporter assays with promoter deletion constructs we show that IFN-beta's inhibitory effects require a region of the promoter between -154 and -72, which contains an AP-1 binding site. Chromatin immunoprecipitation (ChIP) studies indicate that IFN-beta increases histone deacetylase (HDAC)-1 recruitment to the MMP-9 promoter and reduces histone H3 acetylation, in addition to reduced NF-kappaB recruitment. Accordingly, IFN-beta's repressive actions are abrogated in the presence of a type 1 HDAC inhibitor, Trichostatin A (TSA). ChIP analysis shows that IFN-beta induced HDAC1 recruitment to the MMP-9 promoter is lost when the AP-1 binding site is inactivated by a point mutation. Altogether, these results establish that the repression of MMP-9 transcription in response to IFN-beta occurs by the recruitment of HDAC1 to the proximal AP-1 binding site.
Mittelstadt, M. L.(2011). MECHANISM OF TRANSCRIPTIONAL REPRESSION OF MMP-9 BY INTERFERON-β. (Doctoral dissertation). Retrieved from http://scholarcommons.sc.edu/etd/507