Expression of the protein kinase PKR in modulated by IRF-1 and is reduced in 5q- associated leukemias.
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.
Beretta
L
L
Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Gabbay
M
M
Berger
R
R
Hanash
S M
SM
Sonenberg
N
N
D002895:Chromosomes, Human, Pair 5; D004268:DNA-Binding Proteins / Q000502:physiology*; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007938:Leukemia / Q000235:genetics*; D010750:Phosphoproteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017384:Sequence Deletion; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019892:eIF-2 Kinase
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase