The Interferon-inducible Protein Kinase PKR Modulates the Transcriptional Activation of Immunoglobulin κ Gene

Koromilas, Antonis E.; Cantin, Claude; Craig, Andrew W.B.; Jagus, Rosemary; Hiscott, John; Sonenberg, Nahum

doi:10.1074/jbc.270.43.25426

Cited by 41 publications

(33 citation statements)

References 75 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The induction of the cell adhesion molecules VCAM and E-selectin by dsRNA is also mediated through a PKR-dependent pathway (282; S Bandyopadhyay & BRG Williams, unpublished data). Induction of the immunoglobulin κ gene by LPS or IFNγ is mediated by PKR, probably through activation of IRF1 (283).…”

Section: Pkrmentioning

confidence: 99%

How Cells Respond to Interferons

Stark

Kerr

Williams

et al. 1998

Annu. Rev. Biochem.

3,626

3,170

View full text Add to dashboard Cite

Interferons play key roles in mediating antiviral and antigrowth responses and in modulating immune response. The main signaling pathways are rapid and direct. They involve tyrosine phosphorylation and activation of signal transducers and activators of transcription factors by Janus tyrosine kinases at the cell membrane, followed by release of signal transducers and activators of transcription and their migration to the nucleus, where they induce the expression of the many gene products that determine the responses. Ancillary pathways are also activated by the interferons, but their effects on cell physiology are less clear. The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interferons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained. CONTENTS

show abstract

Section: Pkrmentioning

confidence: 99%

How Cells Respond to Interferons

Stark

Kerr

Williams

et al. 1998

Annu. Rev. Biochem.

3,626

3,170

View full text Add to dashboard Cite

show abstract

“…36 and references therein) and malignant transformation (12). At least some of the effects of PKR on gene regulation do not appear to be mediated by changes in eIF2␣ phosphorylation, suggesting that phosphorylation of other proteins may mediate these effects (36). Finally, mice deficient in PKR are impaired in cell signaling pathways including their interferon-␥ and double-stranded RNA-induced antiviral response (11), although these effects are not observed in all PKR null mice (37).…”

Section: Fig 5 Immunodetection Of Human Pkr Using Anti-phosphotyrosmentioning

confidence: 99%

“…In addition, overexpression of catalytically inactive mutants of PKR leads to heightened viral sensitivity (35), altered gene regulation (Ref. 36 and references therein) and malignant transformation (12). At least some of the effects of PKR on gene regulation do not appear to be mediated by changes in eIF2␣ phosphorylation, suggesting that phosphorylation of other proteins may mediate these effects (36).…”

Section: Fig 5 Immunodetection Of Human Pkr Using Anti-phosphotyrosmentioning

confidence: 99%

The Interferon-induced Double-stranded RNA-activated Protein Kinase PKR Will Phosphorylate Serine, Threonine, or Tyrosine at Residue 51 in Eukaryotic Initiation Factor 2α

Lü

O'Hara

Trieselmann

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

The family of eukaryotic initiation factor 2␣ (eIF2␣) protein kinases plays an important role in regulating cellular protein synthesis under stress conditions. The mammalian kinases PKR and HRI and the yeast kinase GCN2 specifically phosphorylate Ser-51 on the ␣ subunit of the translation initiation factor eIF2. By using an in vivo assay in yeast, the substrate specificity of these three eIF2␣ kinases was examined by substituting Ser-51 in eIF2␣ with Thr or Tyr. In yeast, phosphorylation of eIF2 inhibits general translation but derepresses translation of the GCN4 mRNA. All three kinases phosphorylated Thr in place of Ser-51 and were able to regulate general and GCN4-specific translation. In addition, both PKR and HRI were found to phosphorylate eIF2␣-S51Y and stimulate GCN4 expression. Isoelectric focusing analysis of eIF2␣ followed by detection using anti-eIF2␣ and anti-phosphotyrosine-specific antibodies demonstrated that PKR and HRI phosphorylated eIF2␣-S51Y on Tyr in vivo. These results provide new insights into the substrate recognition properties of the eIF2␣ kinases, and they are intriguing considering the potential for alternate substrates for PKR in cellular signaling and growth control pathways.The human interferon-induced double-stranded RNA-activated protein kinase PKR, which functions in the cellular antiviral defense mechanism, is a member of a family of structurally related Ser/Thr kinases that specifically phosphorylate Ser-51 on the ␣ subunit of the translation initiation factor eIF2 1 (1, 2). The binding of double-stranded RNA, thought to be generated during viral infections, is proposed to alter the conformation of PKR and activate the kinase to autophosphorylate (1, 2). The active, phosphorylated form of PKR can then phosphorylate eIF2␣ on Ser-51 and convert eIF2 into an inhibitor of its guanine nucleotide exchange factor eIF2B, resulting in the inhibition of translation initiation (1, 2). The other members of the eIF2␣ kinase family are the mammalian heme-regulated inhibitor of translation (HRI) that is activated by heme deprivation, the apparently ubiquitous kinase GCN2, first identified in yeast but also found in flies and mammals, which is activated under conditions of amino acid or purine nucleotide deprivation (1-4), and the newly identified mammalian kinase PERK or PEK, a transmembrane kinase located in the endoplasmic reticulum that is activated under conditions of endoplasmic reticulum stress (5, 6). In the yeast Saccharomyces cerevisiae, low level phosphorylation of eIF2␣ by GCN2 alters the pattern of translation reinitiation on the GCN4 mRNA and induces GCN4 expression (2). Increased synthesis of GCN4, a transcriptional activator of amino acid biosynthetic genes, enables cells to withstand amino acid starvation conditions. The mammalian eIF2␣ kinases PKR and HRI can substitute for GCN2 in yeast to phosphorylate eIF2␣ and stimulate GCN4 translation (7). In addition, high level phosphorylation of eIF2␣ in yeast by mutationally hyperactivated alleles of GCN2 or by overexpression of PK...

show abstract

“…1 c and f ). Because PKR has been previously implicated in mediating induction of genes by LPS (13)(14)(15) and because LPS also activates similar signaling pathways as TNF-␣ (e.g. stress-activated kinase activation and ceramide generation; refs.…”

Section: Pkr O/o Mefs Are Resistant To Stress-induced Apoptosismentioning

confidence: 99%

A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis

Der

Yang

Weissmann

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

370

253

View full text Add to dashboard Cite

Apoptosis occurs in response to different cellular stresses, including viral infection, inf lammatory cytokines, growth factor deprivation, and UV light, but it is unclear whether these inducers share a common mechanism of induction. The interferon-induced, double-stranded RNAactivated protein kinase (PKR) has been implicated in processes that rely on apoptosis as control mechanisms in vivo, including antiviral activities, cell growth regulation, and tumorigenesis. Here we report that mouse embryo fibroblasts from mutant mice containing homozygous deletions in the PKR gene (Pkr o/o mice) were resistant to apoptotic cell death in response to double-stranded RNA, tumor necrosis factor-␣, or lipopolysaccharide. The mechanism underlying the suppression of apoptosis in the Pkr o/o cells could be attributed to defects in the activation of DNA-binding activity for the transcription factor interferon regulatory factor-1 and in Fas mRNA induction. Thus, these results provide genetic evidence implicating a requirement for PKR in mediating different forms of stress-related apoptosis.

show abstract

The Interferon-inducible Protein Kinase PKR Modulates the Transcriptional Activation of Immunoglobulin κ Gene

Abstract: PKR is an interferon (IFN)-

Cited by 41 publications

References 75 publications

How Cells Respond to Interferons

How Cells Respond to Interferons

The Interferon-induced Double-stranded RNA-activated Protein Kinase PKR Will Phosphorylate Serine, Threonine, or Tyrosine at Residue 51 in Eukaryotic Initiation Factor 2α

A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis

Contact Info

Product

Resources

About