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Published online before print May 13, 2005

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0205112

Received for publication February 23, 2005.
Revised April 20, 2005.
Accepted for publication April 25, 2005.

Article

Interferon--activated STAT-1 suppresses MMP-9 gene transcription by sequestration of the coactivators CBP/p300

Department of Cell Biology, University of Alabama at Birmingham

^@ To whom correspondence should be addressed. E-mail: tika{at}uab.edu.

	Abstract

Interferon- (IFN-) is a pleiotropic cytokine involved in aspects of immune regulation, cell proliferation, and host defense mechanisms directed toward various cancers. Some of the biological functions of IFN- are achieved through inhibition of gene expression, although the mechanisms by which IFN- suppresses gene transcription are poorly understood. Herein, we demonstrate the molecular basis by which IFN- mediates suppression of the matrix metalloproteinase-9 (MMP-9) gene. IFN--activated signal transducer and activator of transcription 1 (STAT-1) suppresses MMP-9 gene transcription, which is dependent on phosphorylation of tyrosine 701 but not phosphorylation of serine 727. The coactivator cyclic AMP response element-binding protein-binding protein (CBP) is an important component of induction of MMP-9 gene transcription. IFN- induces the in vivo association of STAT-1 and CBP and decreases the association of CBP to the MMP-9 promoter. IFN- does not influence the stability of CBP nor does IFN- affect chromatin-remodeling events on the MMP-9 promoter. IFN- inhibits the assembly of the MMP-9 transcription complex by suppressing H3/H4 acetylation and inhibiting recruitment of Pol II to the MMP-9 promoter. These findings indicate that IFN-/STAT-1 exert their inhibitory effects by affecting multiple aspects of MMP-9 gene transcription.

Key Words: cytokines • transcription factors • gene regulation • signal transduction