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

Abstract

Interferon-gamma (IFN-gamma) 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-gamma are achieved through inhibition of gene expression, although the mechanisms by which IFN-gamma suppresses gene transcription are poorly understood. Herein, we demonstrate the molecular basis by which IFN-gamma mediates suppression of the matrix metalloproteinase-9 (MMP-9) gene. IFN-gamma-activated signal transducer and activator of transcription-1alpha (STAT-1alpha) 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-gamma induces the in vivo association of STAT-1alpha and CBP and decreases the association of CBP to the MMP-9 promoter. IFN-gamma does not influence the stability of CBP nor does IFN-gamma affect chromatin-remodeling events on the MMP-9 promoter. IFN-gamma 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-gamma/STAT-1alpha exert their inhibitory effects by affecting multiple aspects of MMP-9 gene transcription.

Signal Transducer and Activator of Transcription 1 Activation in Endothelial Cells Is a Negative Regulator of Angiogenesis

“…IFN-g activation of STAT1 may sequester coactivators, such as cAMP-responsive element binding protein-binding protein (CBP)/p300, similar to the mechanism by which IFN-g suppresses MMP-9 gene expression (39). IFN-g induces the in vivo association of STAT1 and CBP and decreases the association of CBP to the MMP-9 promoter.…”

Interferon‐γ regulation of TNFα‐induced matrix metalloproteinase 3 expression and migration of human glioma T98G cells

“…34,35 Of these, the chromatin binding protein CBP/ p300, as a major cofactor of the transcription complex, was suggested to play an important role in MMP-9 gene transcription. 36 It is not known whether CBP/p300 is involved in MMP-3 regulation. To further elaborate the underlying mechanisms of IFNg-induced inhibition of MMP-3 expression, it would be interesting to investigate whether CBP/p300 plays a role in MMP-3 expression and whether IFNg interferes with activation of the chromatin complex.…”

Mechanism of Interferon-gamma mediated down-regulation of Interleukin-10 gene expression

“…Also, IFN was shown to be able to down-regulate C/EBPα IFN was shown to down-regulate the IL-1 gene in murine macrophages but it was unable to do so in Stat1 -/-animals (De Boer et al, 2001). Furthermore, IFN suppresses MMP-9 via Stat1 (Ma et al, 2001b) and this appears to be due to sequestration of CBP/p300 such that this coactivator is not available for transcription of the MMP-9 gene (Ma et al, 2005).…”