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  • Original Paper
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An IFN regulatory factor-2 DNA-binding domain dominant negative mutant exhibits altered cell growth and gene expression

Oncogene volume 19, pages 1411–1418 (2000)Cite this article

Abstract

In order to study interferon regulatory factor (IRF) family mediation of cell growth regulation, we established U937 cell lines stably transfected with a truncated form of IRF-2 lacking the transcriptional repressor domain. The truncated IRF-2 contained the DNA binding domain (DBD) and bound the ISRE. Phenotypically, the IRF-2 DBD transfectants exhibited reduced cell growth, altered morphology and increased cell death. Consistent with alterations in growth characteristics, the IRF-2 DBD transfectants constitutively expressed higher levels of the cyclin dependent kinase inhibitor p21WAF1/Cip1 than did control clones. The level of p21WAF1/Cip1 expression was positively correlated with the level of DBD expressed, as well as with the level of growth inhibition in these clones. DBD expression also correlated with expression of other members of the growth regulatory complex, cyclin dependent kinase 2 and cyclin A, but not proliferating cell nuclear antigen. These results imply active repression by IRF-2 to keep p21WAF1/Cip1 transcriptionally silent.

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Abbreviations

IFNÏ„:

interferon tau

IFNα:

interferon alpha

ISRE:

IFN-stimulated response element

DBD:

DNA-binding domain

IRF-2:

interferon regulatory factor 2

ICSBP:

interferon consensus sequence-binding protein

2′5′ OAS:

2′5′ oligoadenylate synthetase

EMSA:

electrophoretic mobility shift assay

UCR:

upstream conserved region

Cdk:

cyclin dependent kinase

PCNA:

proliferating cell nuclear antigen

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Acknowledgements

We thank Drs Mark Hayes and Joy Williams (Food and Drug Administration) for their insightful manuscript review. This work was supported in part by a predoctoral fellowship to YR Rubinstein from the National Institute of Child Health and Development and in part by American Heart Association grant 94011550 to CH Pontzer.

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Authors and Affiliations

  1. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, 20742, Maryland, MD, USA

    Y R Rubinstein & C H Pontzer

  2. Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, 20814, Maryland, MD, USA

    P H Driggers

  3. Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, NIH, Bethesda, 20892, Maryland, MD, USA

    V V Ogryzko & K Ozato

  4. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, 20892, Maryland, USA

    A M Thornton

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  1. Y R Rubinstein
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  2. P H Driggers
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Rubinstein, Y., Driggers, P., Ogryzko, V. et al. An IFN regulatory factor-2 DNA-binding domain dominant negative mutant exhibits altered cell growth and gene expression. Oncogene 19, 1411–1418 (2000). https://doi.org/10.1038/sj.onc.1203435

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