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

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 bio-logical functions of IFN- are achieved through inhibition of gene expression, although the mech-anisms by which IFN- suppresses gene transcrip-tion are poorly understood. Herein, we demon-strate 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) sup-presses MMP-9 gene transcription, which is depen-dent 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 in-hibiting recruitment of Pol II to the MMP-9 pro-moter. These findings indicate that IFN-/ STAT-1 exert their inhibitory effects by affecting multiple aspects of MMP-9 gene transcription. J