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Expression of the protein kinase PKR in modulated by IRF-1 and is reduced in 5q- associated leukemias.

Abstract
The transcription factor IRF-1 (interferon regulatory factor 1) is an activator of type I interferon and interferon-inducible genes. IRF-1 manifests tumor suppressor activity. Its overexpression results in inhibition of cell growth, and deletions of the IRF-1 gene were demonstrated in a number of human leukemias and myelodysplasias. Although the mechanism by which IRF-1 affects cell growth is unknown, it is believed that IRF-1 activates a set of genes that negatively regulate cell growth. The double-stranded RNA-dependent protein kinase (PKR), which is an interferon-inducible gene, contains a promoter element for the binding of IRF-1 and exhibits antiproliferative properties. Consequently, we investigated the role of IRF-1 in PKR expression. Here, we show that in IRF-1-deficient embryonic fibroblasts, PKR expression is reduced relative to wild-type cells. This result predicts diminished expression of PKR as a potential consequence of deletion of the IRF-1 gene in human leukemias. We show that cells of the human leukemic U937 cell line contain a deletion of one IRF-1 gene and express low levels of PKR. We demonstrate that upregulation of IRF-1 expression in U937 cells by transfection is sufficient to induce PKR expression. We also found a marked reduction in the expression of PKR in blood samples from two patients with myelodysplasias, carrying a deletion of chromosome 5q, a locus to which IRF-1 was mapped. These results show that IRF-1 activates PKR expression and suggest that loss of one allele of the IRF-1 gene is sufficient to affect PKR expression. Therefore, PKR is a strong candidate for a mediator of the tumor suppressor activity of IRF-1.
AuthorsL Beretta, M Gabbay, R Berger, S M Hanash, N Sonenberg
JournalOncogene (Oncogene) Vol. 12 Issue 7 Pg. 1593-6 (Apr 04 1996) ISSN: 0950-9232 [Print] England
PMID8622878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA-Binding Proteins
  • IRF1 protein, human
  • Interferon Regulatory Factor-1
  • Phosphoproteins
  • Transcription Factors
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
Topics
  • Chromosomes, Human, Pair 5
  • DNA-Binding Proteins (physiology)
  • Fibroblasts (enzymology)
  • Gene Expression Regulation, Enzymologic (physiology)
  • Humans
  • Interferon Regulatory Factor-1
  • Leukemia (genetics)
  • Phosphoproteins (physiology)
  • Protein Serine-Threonine Kinases (genetics)
  • Sequence Deletion
  • Transcription Factors (physiology)
  • Tumor Cells, Cultured
  • eIF-2 Kinase

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