Negative regulation of NF-kappaB signaling by PIAS1.
The NF-kappaB family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes. The proper regulation of NF-kappaB activity is critical, since abnormal NF-kappaB signaling is associated with a number of human illnesses, such as chronic inflammatory diseases and cancer. We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-kappaB. Upon cytokine stimulation, the p65 subunit of NF-kappaB translocates into the nucleus, where it interacts with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-kappaB-dependent gene activation. PIAS1 blocks the DNA binding activity of p65 both in vitro and in vivo. Consistently, chromatin immunoprecipitation assays indicate that the binding of p65 to the promoters of NF-kappaB-regulated genes is significantly enhanced in Pias1-/- cells. Microarray analysis indicates that the removal of PIAS1 results in an increased expression of a subset of NF-kappaB-mediated genes in response to tumor necrosis factor alpha and lipopolysaccharide. Consistently, Pias1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-kappaB.
Liu
Bin
B
Division of Hematology-Oncology, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678, USA.
Yang
Randy
R
Wong
Kelly A
KA
Getman
Crescent
C
Stein
Natalie
N
Teitell
Michael A
MA
Cheng
Genhong
G
Wu
Hong
H
Shuai
Ke
K
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D016328:NF-kappa B / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA; D014158:Transcription, Genetic / Q000235:genetics*; D000097782:NF-kappaB-Inducing Kinase
D016207:Cytokines; D016328:NF-kappa B; D050828:Protein Inhibitors of Activated STAT; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D051996:Transcription Factor RelA; D000097782:NF-kappaB-Inducing Kinase; C494211:Pias1 protein, mouse