PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4.
In response to interleukin 12 (IL-12) stimulation, a latent cytoplasmic transcription factor, Stat4 (signal transducer and activator of transcription 4), becomes tyrosine-phosphorylated and translocates into the nucleus where it binds to DNA to activate transcription. Cofactors that can directly bind and regulate Stat4 activity have not been described. We report here that PIASx, a member of the protein inhibitor of activated STAT (PIAS) family, is a negative regulator of Stat4. PIASx becomes associated with Stat4 following IL-12 stimulation in vivo. PIASx inhibits IL-12-stimulated and Stat4-dependent gene activation in human T cells. PIASx does not inhibit the DNA binding activity of Stat4. Instead PIASx is present in the Stat4-DNA binding complex. Finally the inhibitory activity of PIASx on Stat4-mediated gene activation is abolished by the histone deacetylase inhibitor trichostatin A. Our results suggest that PIASx may function as a co-repressor of Stat4.
Arora
Taruna
T
Division of Hematology-Oncology, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678, USA.
Liu
Bin
B
He
Hongchin
H
Kim
Jenny
J
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
Modlin
Robert L
RL
Shuai
Ke
K
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D016898:Interferon-alpha / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016898:Interferon-alpha; D009841:Oligonucleotides; C501001:PIAS2 protein, human; D050828:Protein Inhibitors of Activated STAT; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; C012589:trichostatin A; D014443:Tyrosine; D004247:DNA; D008156:Luciferases; D006655:Histone Deacetylases