Upregulation of STAT1 protein in cells lacking or expressing mutants of the double‐stranded RNA‐dependent protein kinase PKR

Tam, Nancy Wai Ning; Ishii, Tetsu; Li, Suiyang; Wong, Andrew; Cuddihy, Andrew; Koromilas, Antonis E.

doi:10.1046/j.1432-1327.1999.00360.x

Cited by 20 publications

(11 citation statements)

References 28 publications

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“…Ubiquitinylation of STAT1 [88] was reported to be mediated by the E3 ligases c-CBL (Casitas B-lineage lymphoma) [89] or SLIM (STAT-interacting LIM protein) [90]. SLIM acts in concert with PKR (RNA-dependent A c c e p t e d M a n u s c r i p t 8 protein kinase) [91,92] and this E3 is also critical for STAT1 degradation in mammary epithelial tumor cells exposed to the secreted glycoprotein Osteopontin [93]. Since STAT1 promotes its own synthesis strongly after its induction via IFNs [38,75,94,95], stimulusinduced degradation of this protein is hardly or not at all detectable.…”

Section: Diverse Posttranslational Modifications Of Stat1mentioning

confidence: 99%

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

Krämer¹,

Heinzel²

2010

Molecular and Cellular Endocrinology

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Section: Diverse Posttranslational Modifications Of Stat1mentioning

confidence: 99%

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

Krämer¹,

Heinzel²

2010

Molecular and Cellular Endocrinology

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“…MxA is a dynamin superfamily transport GTPase that exhibits antiviral activity against several RNA viruses (21). Stat1 is activated by both the type I (IFN-a and -b) and II (IFN-g) interferon signaling cascades, but the overall expression levels of this transcription factor in the unactivated state may modify cellular responses to interferons (22,23). PKR is a double-stranded RNA-activated serine-threonine kinase that inhibits protein synthesis and mediates other cellular responses to viral infection or inflammatory stimuli (21).…”

Section: Adv Infection Inhibits Ifn-a-dependent Gene Expressionmentioning

confidence: 99%

Inhibition of Jak1-Dependent Signal Transduction in Airway Epithelial Cells Infected with Adenovirus

Shi

Ramaswamy²,

Manzel³

et al. 2007

Am J Respir Cell Mol Biol

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Adenoviral evolution has generated mechanisms to resist host cell defense systems, but the biochemical basis for evasion of multiple antiviral pathways in the airway by adenoviruses is incompletely understood. We hypothesized that adenoviruses modulate airway epithelial responses to type I interferons by altering the levels and activation of specific Janus family kinase-signal transducer and activator of transcription (JAK-STAT) signaling components. In this study, specific effects of adenovirus type 5 (AdV) on selected JAK-STAT signal transduction pathways were identified in human tracheobronchial epithelial cells, with focus on type I interferondependent signaling and gene expression. We found that wild-type AdV infection inhibited IFN-a-induced expression of antiviral proteins in epithelial cells by blocking phosphorylation of the Stat1 and Stat2 transcription factors that are required for activation of type I interferon-dependent genes. These effects correlated with AdVinduced down-regulation of expression of the receptor-associated tyrosine kinase Jak1 through a decrease in Jak1 mRNA levels. Phosphorylation of Stat3 in response to IL-6 and oncostatin M was also lost in AdV-infected cells, indicating loss of epithelial cell responses to other cytokines that depend on Jak1. In contrast, IL-4-and IL-13-dependent phosphorylation of Stat6 was not affected during AdV infection, indicating that the virus modulates specific signaling pathways, as these Stat6-activating pathways can function independent of Jak1. Taken together, the results indicate that AdV down-regulates host epithelial cell Jak1 to assure inhibition of the antiviral effects of multiple mediators to subvert airway defense responses and establish a productive infection.

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“…T7 vaccinia virus transient transfections were carried out using the recombinant vaccinia virus, vTF7-3, encoding the bacteriophage T7 RNA polymerase (20). In vivo [ 35 S]methionine experiments were performed as previously described (21). pBABE, pBABE-HA-STAT1␣ WT, or TM STAT1…”

Section: Cell Culture and Transfections-hela S3 U3a Stat1mentioning

confidence: 99%

Enhanced Antiviral and Antiproliferative Properties of a STAT1 Mutant Unable to Interact with the Protein Kinase PKR

Wong

Durbin²,

et al. 2001

Journal of Biological Chemistry

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We have previously reported a physical association between STAT1 and the protein kinase double-stranded RNA-activated protein kinase (PKR). PKR inhibited STAT1 function in a manner independent of PKR kinase activity. In this report, we have further characterized the properties of both molecules by mapping the sites of their interaction. A STAT1 mutant unable to interact with PKR displays enhanced interferon ␥ (IFN-␥)-induced transactivation capacity compared with STAT1. This effect appears to be mediated by the higher capacity of STAT1 mutant to heterodimerize with STAT3. Furthermore, expression of STAT1 mutant in STAT1 ؊/؊ cells enhances both the antiviral and antiproliferative effects of IFNs as opposed to STAT1. We also provide evidence that STAT1 functions as an inhibitor of PKR in vitro and in vivo. That is, phosphorylation of eIF-2␣ is enhanced in STAT1 ؊/؊ than STAT1 ؉/؉ cells in vivo, and this correlates with higher activation capacity of PKR in STAT1 ؊/؊ cells. Genetic experiments in yeast demonstrate the inhibition of PKR activation and eIF-2␣ phosphorylation by STAT1 but not by STAT1 mutant. These data substantiate our previous findings on the inhibitory effects of PKR on STAT1 and implicate STAT1 in translational control through the modulation of PKR activation and eIF-2␣ phosphorylation.Cytokines and growth factors exert a diverse range of biological activities, from host defense, growth regulation, to immunomodulation. Upon ligand binding to cell-surface receptors, JAK 1 kinases are activated and proceed to phosphorylate the receptor on tyrosine residues, which then function as docking sites for cytoplasmic transcription factors of the STAT family (1, 2). STATs are subsequently activated by tyrosine phosphorylation, dimerize by phosphotyrosyl⅐SH2 interactions, and translocate to the nucleus to induce transcription of cytokineresponsive genes (3). A single tyrosine phosphorylation site in the carboxyl-terminal activation domain is absolutely essential for STAT dimerization and DNA binding (3), whereas

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Upregulation of STAT1 protein in cells lacking or expressing mutants of the double‐stranded RNA‐dependent protein kinase PKR

Cited by 20 publications

References 28 publications

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

Inhibition of Jak1-Dependent Signal Transduction in Airway Epithelial Cells Infected with Adenovirus

Enhanced Antiviral and Antiproliferative Properties of a STAT1 Mutant Unable to Interact with the Protein Kinase PKR

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