Negative regulation of NF-kappaB signaling by PIAS1

Division of Hematology-Oncology, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 03/2005; 25(3):1113-23. DOI: 10.1128/MCB.25.3.1113-1123.2005
Source: PubMed


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.

10 Reads
  • Source
    • "All other cells were maintained in RPMI supplemented with 10% FBS and 1% Penicillin/Streptomycin. Stem Cell Media (SCM) is composed of DMEM/F-12 (Cellgro) supplemented with 0.4% BSA, 1% Penicillin/Streptomycin, 2 mM Glutamine, 25 ng/ml human EGF (R&D), 25 ng/ml human basic FGF (R&D) and 5 ug/ml human insulin (Sigma). The following agents have also been used: Heregulin (Upstate), anti-pPIAS1 (Ser90-phosphorylated PIAS1) [22], polyclonal anti-PIAS1 [20], [51]; anti-Tubulin (Sigma), anti-WNT5A/B (Cell Signaling) and recombinant murine WNT5A protein (R&D). This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Epigenetic gene silencing by histone modifications and DNA methylation is essential for cancer development. The molecular mechanism that promotes selective epigenetic changes during tumorigenesis is not understood. We report here that the PIAS1 SUMO ligase is involved in the progression of breast tumorigenesis. Elevated PIAS1 expression was observed in breast tumor samples. PIAS1 knockdown in breast cancer cells reduced the subpopulation of tumor-initiating cells, and inhibited breast tumor growth in vivo. PIAS1 acts by delineating histone modifications and DNA methylation to silence the expression of a subset of clinically relevant genes, including breast cancer DNA methylation signature genes such as cyclin D2 and estrogen receptor, and breast tumor suppressor WNT5A. Our studies identify a novel epigenetic mechanism that regulates breast tumorigenesis through selective gene silencing.
    PLoS ONE 02/2014; 9(2):e89464. DOI:10.1371/journal.pone.0089464 · 3.23 Impact Factor
  • Source
    • "Emerging role of the ubiquitin-like proteins in TLR signaling PIAS1 (protein inhibitor of activated STAT1) is a putative candidate of the SUMO E3 ligases. Previously, it was demonstrated that PIAS1 is a novel negative regulator of the NF-kB signaling, indicating that SUMOylation could modulate innate immunity [63]. To corroborate it, a yeast two-hybrid screen fished out the SUMO conjugating enzyme Ubc9, which specifically bound to IkBa. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein post-translational modifications (PTMs) are central to the host innate immune regulations. Dynamically, PTMs fine-tune the spatial and temporary responses of immune- and non-immune-cells, in accordance with extracellular and intracellular stresses. Ubiquitin and ubiquitin-like proteins (Ubls) are emerging as the important multi-functional signals, controlling the activation, stability, affinity and location of many signaling proteins. Recent investigations, at the molecular-cellular-animal models, have shed new light on the versatility of the ubiquitin, SUMO and ISG15, for shaping the strength and duration of the innate immune responses. This review summarizes our current knowledge on the functions and regulatory mechanisms of the ubiquitin and Ubls in the innate immunity, the first line of host defense against microbial infection.
    Cytokine & growth factor reviews 08/2013; 24(6). DOI:10.1016/j.cytogfr.2013.07.002 · 5.36 Impact Factor
  • Source
    • "PIAS1 has also been shown to bind directly to STAT1 and repress STAT1 transcriptional activity. PIAS1−/− mice are more sensitive to inflammatory responses mediated by interferon-γ (IFN-γ) or interferon-β (IFN-β) [12, 22, 23], and are hypersensitive to lipopolysaccharides (LPS) that induces endotoxic shock [22]. The STAT1 and NF-κB activities are increased in PIAS1−/− mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the exact mechanism through which NADPH oxidases (Nox's) generate reactive oxygen species (ROS) is still not completely understood, it is widely considered that ROS accumulation is the cause of oxidative stress in endothelial cells. Increasing pieces of evidence strongly indicate the role for ROS in endothelial inflammation and dysfunction and subsequent development of atherosclerotic plaques, which are causes of various pathological cardiac events. An overview for a causative relationship between ROS and endothelial inflammation will be provided in this review. Particularly, a crucial role for specific protein SUMOylation in endothelial inflammation will be presented. Given that SUMOylation of specific proteins leads to increased endothelial inflammation, targeting specific SUMOylated proteins may be an elegant, effective strategy to control inflammation. In addition, the involvement of ROS production in increasing the risk of recurrent coronary events in a sub-group of non-diabetic, post-infarction patients with elevated levels of HDL-cholesterol will be presented with the emphasis that elevated HDL-cholesterol under certain inflammatory conditions can lead to increased incidence of cardiovascular events.
    09/2012; 2012(1389):678190. DOI:10.1155/2012/678190
Show more

Preview (2 Sources)

10 Reads
Available from