 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
REPORTE CORTO/SHORT REPORT Presented in the Congress Biotecnologia Habana 94. La Habana, Cuba, Nov. 28 - Dec. 3, 1994 THE ROLE OF PKR IN dsRNA AND INTERFERON SIGNAL TRANSDUCTION Bryan R.G. Williams and Aseem Kumar.
Department of Cancer Biology, Research Institute, Cleveland Clinic Foundation, Cleveland, OH44195, USA.
Code Number: BA95043
File Sizes:
Text: 3K
No associated graphics
The signal transduction pathway involved in the induction of
interferon (IFN) genes by viruses or double-stranded RNA (dsRNA)
is not well understood. One of the factors necessary for
transcriptional activation of the IFN-beta gene is Nuclear
Factor-kappa B (NF-kB), the activation of which is triggered by
dsRNA.It has previously been suggested that the dsRNA activated p68 kinase may act as an inducer receptor, transducing the signal from dsRNA to NF-kB through prhosphorylation of the inhibitor IkB. We show that PKR directly phosphorylates the inhibitor of NK-kB. We show that PKR directly phosphorylates the inhibitor of NF-KB, IkB-alpha (MAD-3) thereby activating NF-kB DNA binding activity in vitro. Analysis of IkB-alpha protein from dsRNA-treated mouse macrophages indicates a dsRNA-dependent alternate phosphoform of IkB-alpha. In cells transfected with a mutant (Lys296-Arg) PKR, dsRNA induction of a kB-dependent promoter construct is blocked supporting a signal transducing role for PKR. Further evidence for such a role was obtained by specifically ablating PKR mRNA in cells and demonstrating that these cells were deficient in dsRNA activation of NF-kB (in collaboration with R. Silverman). Furthermore, in cells derived from mice in wich the PKR gene was homozygously deleted, dsRNA induction of the IFN-beta gene is impaired and NF-kB activation is deficient (in collaboration with C. Weissmann). Taken together these results show that PKR plays a central role in the signal-transduction pathway involved in the induction of IFN-beta gene transcription. dsRNA also activates the transcription of a number of other genes which may also utilize PKR as a signal transducer. Using a combination of genetic ablation and expression of mutant PKR molecules we are presently identifying novel dsRNA activated, PKR-mediated regulators of transcription.
Copyright 1995 Sociedad Iberolatinoamericana de Biotecnologia Aplicada a la Salud
|
| |||||||||
