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.
","abstract_html":"<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>","abstract_has_math":false,"creators":["Mittelstadt, Megan Laurel"],"institution":null,"degree_name":"Ph.D.","degree_level":"Campus Access Dissertation","degree_discipline":"Biological Sciences","degree_department":null,"school":null,"contributors":["Rekha C Patel"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-01-01T08:00:00Z","date_published":"2011-01-01T08:00:00Z","updated_at":"2026-07-24T04:38:07Z","subjects":["Life Sciences","Medicine and Health Sciences","Physical Sciences and Mathematics","AP-1","HDAC1","interferon","MMP-9"],"languages":[],"rights":["© 2011, Megan Laurel Mittelstadt"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://scholarcommons.sc.edu/etd/507","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Rekha C Patel"]},{"key":"dc:creator","label":"Author","values":["Mittelstadt, Megan Laurel"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_discipline","label":"Discipline","values":["Biological Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Campus Access Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Life Sciences","Medicine and Health Sciences","Physical Sciences and Mathematics","AP-1","HDAC1","interferon","MMP-9"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["© 2011, Megan Laurel Mittelstadt"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://scholarcommons.sc.edu/etd/507"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["MECHANISM OF TRANSCRIPTIONAL REPRESSION OF MMP-9 BY INTERFERON-β"]}]}],"canonical_facts":{"dc:contributor":["Rekha C Patel"],"dc:creator":["Mittelstadt, Megan Laurel"],"dc:description.abstract":["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.
"],"dc:identifier":["https://scholarcommons.sc.edu/etd/507"],"dc:rights":["© 2011, Megan Laurel Mittelstadt"],"dc:subject":["Life Sciences","Medicine and Health Sciences","Physical Sciences and Mathematics","AP-1","HDAC1","interferon","MMP-9"],"dc:title":["MECHANISM OF TRANSCRIPTIONAL REPRESSION OF MMP-9 BY INTERFERON-β"],"thesis:degree_discipline":["Biological Sciences"],"thesis:degree_level":["Campus Access Dissertation"],"thesis:degree_name":["Ph.D."]},"updated_at":"2026-07-24T04:38:07Z"}