MECHANISM OF TRANSCRIPTIONAL REPRESSION OF MMP-9 BY INTERFERON-β

<p>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.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Campus Access Dissertation

Discipline thesis:degree_discipline

Biological Sciences

Year

2011

Author dc:creator

• Mittelstadt, Megan Laurel

Contributors dc:contributor

• Rekha C Patel

• Life Sciences
• Medicine and Health Sciences
• Physical Sciences and Mathematics
• AP-1
• HDAC1
• interferon
• MMP-9

Statement dc:rights

• © 2011, Megan Laurel Mittelstadt

Repository record dc:identifier

https://scholarcommons.sc.edu/etd/507

OAI identifier oai:identifier

oai:scholarcommons.sc.edu:etd-1508