Interferon-gamma-activated STAT-1alpha suppresses MMP-9 gene transcription by sequestration of the coactivators CBP/p300.
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.
Ma
Zhendong
Z
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
Chang
Mi Jung
MJ
Shah
Reesha C
RC
Benveniste
Etty N
EN
D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D050882:CREB-Binding Protein; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004257:DNA Polymerase II / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D020218:Response Elements / Q000502:physiology; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000970:Antineoplastic Agents; D006657:Histones; D050832:Interferon-Stimulated Gene Factor 3; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C079868:gamma interferon activation factor; D007371:Interferon-gamma; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D004257:DNA Polymerase II; D020780:Matrix Metalloproteinase 9