Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300.
We report that interferon gamma (IFN-gamma) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors, apparently as a result of competition between AP-1/ets factors and activated STAT1 for limiting amounts of CBP and p300. Consistent with this model, STAT1 alpha interacts directly with CBP in cells, and microinjection of anti-CBP and anti-p300 antibodies blocks transcriptional responses to IFN-gamma. Cells lacking STAT1 fail to inhibit AP-1/ets activity, and overexpression of CBP both potentiates IFN-gamma-dependent transcription and relieves AP-1/ets repression. Thus, CBP and p300 integrate both positive and negative effects of IFN-gamma on gene expression by serving as essential coactivators of STAT1 alpha, modulating gene-specific responses to simultaneous activation of two or more signal transduction pathways.
Horvai
A E
AE
Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla 92093-0651, USA.
Xu
L
L
Korzus
E
E
Brard
G
G
Kalafus
D
D
Mullen
T M
TM
Rose
D W
DW
Rosenfeld
M G
MG
Glass
C K
CK
D000123:Acetyltransferases; D000818:Animals; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004336:Drug Antagonism; D051548:Histone Acetyltransferases; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D050794:STAT1 Transcription Factor; D051122:Scavenger Receptors, Class B; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D050882:CREB-Binding Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D007371:Interferon-gamma; D016173:Macrophage Colony-Stimulating Factor; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D050794:STAT1 Transcription Factor; D051122:Scavenger Receptors, Class B; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494079:STAT1 protein, human; C454739:Scarb1 protein, mouse; C494080:Stat1 protein, mouse; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse