Article

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

ABSTRACT

The NF-κB family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes.
The proper regulation of NF-κB activity is critical, since abnormal NF-κB 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-κB. Upon cytokine stimulation, the p65 subunit of NF-κB translocates into the nucleus, where it interacts
with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-κB-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-κB-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-κB-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-κB.

Full-text preview

Available from: ncbi.nlm.nih.gov
  • 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.
    Full-text · Article · Feb 2014 · PLoS ONE
  • Source
    • "The molecular mechanism that controls the methylation dynamics during HSC differentiation has not been understood. PIAS1 (protein inhibitor of activated STAT1) is a SUMO E3 ligase that binds to chromatin to repress transcription (Shuai & Liu, 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The selective and temporal DNA methylation plays an important role in the self-renewal and differentiation of hematopoietic stem cells (HSCs), but the molecular mechanism that controls the dynamics of DNA methylation is not understood. Here, we report that the PIAS1 epigenetic pathway plays an important role in regulating HSC self-renewal and differentiation. PIAS1 is required for maintaining the quiescence of dormant HSCs and the long-term repopulating capacity of HSC. Pias1 disruption caused the abnormal expression of lineage-associated genes. Bisulfite sequencing analysis revealed the premature promoter demethylation of Gata1, a key myeloerythroid transcription factor and a PIAS1-target gene, in Pias1(-/-) HSCs. As a result, Pias1 disruption caused the inappropriate induction of Gata1 in HSCs and common lymphoid progenitors (CLPs). The expression of other myeloerythroid genes was also enhanced in CLPs and lineage-negative progenitors, with a concurrent repression of B cell-specific genes. Consistently, Pias1 disruption caused enhanced myeloerythroid, but reduced B lymphoid lineage differentiation. These results identify a novel role of PIAS1 in maintaining the quiescence of dormant HSCs and in the epigenetic repression of the myeloerythroid program.
    Preview · Article · Jan 2014 · The EMBO Journal
  • 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.
    Full-text · Article · Aug 2013 · Cytokine & growth factor reviews
Show more