Acetylation of Stat1 modulates NF- ␬ B activity

Georg-Speyer-Haus, D-60596 Frankfurt, Germany.
Genes & Development (Impact Factor: 10.8). 03/2006; 20(4):473-85. DOI: 10.1101/gad.364306
Source: PubMed


Acetylation of signaling molecules can lead to apoptosis or differentiation of carcinoma cells. The molecular mechanisms underlying these processes and the biological role of enzymes mediating the transfer or removal of an acetyl-group are currently under intense investigation. Our study shows that Stat1 is an acetylated protein. Stat1 acetylation depends on the balance between Stat1-associated histone deacetylases (HDACs) and histone acetyltransferases (HATs) such as CBP. Remarkably both inhibitors of HDACs and the cytokine interferon alpha alter this equilibrium and induce Stat1 acetylation. The analysis of Stat1 mutants reveals Lys 410 and Lys 413 as acetylation sites. Experiments with Stat1 mutants mimicking either constitutively acetylated or nonacetylated states show that only acetylated Stat1 is able to interact with NF-kappaB p65. As a consequence, p65 DNA binding, nuclear localization, and expression of anti-apoptotic NF-kappaB target genes decrease. These findings show how the acetylation of Stat1 regulates NF-kappaB activity and thus ultimately apoptosis.

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Available from: Thorsten Heinzel, Apr 18, 2014
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    • "Furthermore, while the interactions with some transcription factors increases the DNA binding of NFκB complexes to target genes, as is observed with STAT3 (Nadiminty et al., 2006), interactions with similar factors (i.e. STAT1) can have the opposite effect, and impair NFκB DNA binding (Kramer et al., 2006). "
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    ABSTRACT: In contrast to other organs, the lung completes a significant portion of its development after term birth. During this stage of alveolarization, division of the alveolar ducts into alveolar sacs by secondary septation, and expansion of the pulmonary vasculature by means of angiogenesis markedly increase the gas exchange surface area of the lung. However, postnatal completion of growth renders the lung highly susceptible to environmental insults such as inflammation that disrupt this developmental program. This is particularly evident in the setting of preterm birth, where impairment of alveolarization causes bronchopulmonary dysplasia, a chronic lung disease associated with significant morbidity. The nuclear factor κ-B (NFκB) family of transcription factors are ubiquitously expressed, and function to regulate diverse cellular processes including proliferation, survival, and immunity. Extensive evidence suggests that activation of NFκB is important in the regulation of inflammation and in the control of angiogenesis. Therefore, NFκB-mediated downstream effects likely influence the lung response to injury and may also mediate normal alveolar development. This review summarizes the main biologic functions of NFκB, and highlights the regulatory mechanisms that allow for diversity and specificity in downstream gene activation. This is followed by a description of the pro and anti-inflammatory functions of NFκB in the lung, and of NFκB-mediated angiogenic effects. Finally, this review summarizes the clinical and experimental data that support a role for NFκB in mediating postnatal angiogenesis and alveolarization, and discusses the challenges that remain in developing therapies that can selectively block the detrimental functions of NFκB yet preserve the beneficial effects. Birth Defects Research, 2014. © 2014 Wiley Periodicals, Inc.
    Birth Defects Research Part A Clinical and Molecular Teratology 03/2014; 100(3). DOI:10.1002/bdra.23233 · 2.09 Impact Factor
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    • "Specifically acetylation on lysine residues 122 and 123 by p300 and PCAF (p300/CBP-associated factor) was shown to reduce the binding of NF-κB to κB promoter regions and facilitate the IκBα-dependent nuclear export (Kiernan et al., 2003). Moreover, the acetylation of Signal Transducers and Activators of Transcription 1 (STAT1) results in the binding of STAT1 to NF-κB and thus reduces NF-κB signaling (Kramer et al., 2006). "
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    ABSTRACT: Histone deacetylase (HDAC) inhibitors are promising new compounds for the therapy of fibrotic diseases. In this study we compared the effect of two HDAC inhibitors, trichostatin A and valproic acid, in an experimental model of kidney fibrosis. In mice, doxorubicin (adriamycin) can cause nephropathy characterized by chronic proteinuria, glomerular damage and interstitial inflammation and fibrosis, as seen in human focal segmental glomerulosclerosis. Two treatment regimens were applied, treatment was either started prior to the doxorubicin insult or delayed until a significant degree of proteinuria and fibrosis was present. Pre-treatment of trichostatin A significantly hampered glomerulosclerosis and tubulointerstitial fibrosis, as did the pre-treatment with valproic acid. In contrast, the development of proteinuria was only completely inhibited in the pre-treated valproic acid group, and not in the pre-treated trichostatin A animals. In the postponed treatment with valproic acid, a complete resolution of established doxorubicin-induced proteinuria was achieved within three days, whereas trichostatin A could not correct proteinuria in such a treatment regimen. However, both postponed regimens have comparable efficacy in maintaining the kidney fibrosis to the level reached at the start of the treatments. Moreover, not only the process of fibrosis, but also renal inflammation was attenuated by both HDAC inhibitors. Our data confirm a role for HDACs in renal fibrogenesis and point towards a therapeutic potential for HDAC inhibitors. The effect on renal disease progression and manifestation can however be different for individual HDAC inhibitors.
    Toxicology and Applied Pharmacology 05/2013; 271(2). DOI:10.1016/j.taap.2013.05.013 · 3.71 Impact Factor
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    • "STAT-1 and p21 are essential proteins that are involved in modulation and regulation of apoptotic process [36,38]. Recent studies have also focussed on HDAC inhibitors and their repressive role on NF-kB dependent genes i.e Bcl-xL, Survivin [40] to control cell proliferation. Thus we have treated A375 cells with chrysin (40 μM) and TSA (4 μM) for 72 h and lysates were subjected to western blot analyses. "
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    ABSTRACT: Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells. Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27). The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays. Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis. Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (-692 to -684) region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating cell cycle progression negatively via the induction of the CDK inhibitor p21WAF1.
    BMC Cancer 05/2012; 12(1):180. DOI:10.1186/1471-2407-12-180 · 3.36 Impact Factor
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