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.
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Authors | L Beretta, M Gabbay, R Berger, S M Hanash, N Sonenberg |
Journal | Oncogene
(Oncogene)
Vol. 12
Issue 7
Pg. 1593-6
(Apr 04 1996)
ISSN: 0950-9232 [Print] England |
PMID | 8622878
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- DNA-Binding Proteins
- IRF1 protein, human
- Interferon Regulatory Factor-1
- Phosphoproteins
- Transcription Factors
- Protein Serine-Threonine Kinases
- eIF-2 Kinase
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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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