The promyelocytic leukemia protein functions as a negative regulator of IFN-gamma signaling.
IFN-gamma is an immunomodulatory cytokine and uses the STAT-1alpha transcription factor to mediate gene expression. The promyelocytic leukemia (PML) protein regulates transcription as an activator or repressor, depending on the gene under investigation. Herein, we examined the influence of PML on IFN-gamma signaling, using PML wild-type (Pml(+/+)) and deficient (Pml(-/-)) mouse embryonic fibroblasts (MEF). Pml(-/-) MEF exhibit enhanced IFN-gamma-induced STAT-1alpha transcriptional activity compared with Pml(+/+) cells. Moreover, reconstitution of PML in Pml(-/-) MEF reduced STAT-1alpha transcriptional activity to levels comparable to Pml(+/+) MEF. Numerous endogenous IFN-gamma-regulated genes were up-regulated in Pml(-/-) MEF compared with Pml(+/+) MEF. IFN-gamma-mediated STAT-1alpha DNA-binding activity was enhanced in Pml(-/-) cells compared with Pml(+/+) cells. Lastly, IFN-gamma enhanced the formation of a PML-STAT-1alpha complex in the nucleus. These data suggest a novel function for PML in the IFN-gamma signaling pathway by inhibiting STAT-1alpha DNA binding and transcriptional activity.
Choi
Youn-Hee
YH
Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA.
Bernardi
Rosa
R
Pandolfi
Pier Paolo
PP
Benveniste
Etty N
EN
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D000071156:Promyelocytic Leukemia Protein; D011485:Protein Binding / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma