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A nuclear tyrosine phosphatase downregulates interferon-induced gene expression
M David1, P M Grimley, D S Finbloom
1Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, Maryland 20892.
Molecular and Cellular Biology
|December 1, 1993
Summary
Interferons activate gene transcription via tyrosine phosphorylation. A nuclear tyrosine phosphatase deactivates these factors, downregulating gene expression and controlling protein localization, revealing a novel regulatory mechanism.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Gene Regulation
Background:
- Alpha and gamma interferons induce early response genes in human cells.
- Interferon-stimulated gene transcription involves specific DNA-binding complexes like ISGF3, GAF, and FcRF gamma.
- Tyrosine phosphorylation is crucial for the assembly of these interferon-activated transcription complexes.
Purpose of the Study:
- To investigate the mechanism of transcriptional downregulation of interferon-induced genes.
- To identify the factors responsible for deactivating interferon-regulated transcription factors.
- To elucidate the role of tyrosine phosphorylation in the nuclear localization of key transcription proteins.
Main Methods:
- Treatment of primary human diploid fibroblasts with interferons.
- Analysis of gene transcription rates over time.
- Characterization of interferon-activated DNA-binding complexes and their components.
Main Results:
- A nuclear tyrosine phosphatase was identified as responsible for deactivating interferon-regulated transcription factors.
- This phosphatase activity leads to the subsequent downregulation of target genes.
- Tyrosine phosphorylation is essential for the nuclear localization of the 91-kDa protein, a component of all three identified transcription complexes.
Conclusions:
- Nuclear tyrosine phosphatase activity represents a novel mechanism for regulating interferon-induced gene transcription.
- This phosphatase plays a critical role in turning off interferon-stimulated gene expression.
- The findings highlight the dynamic interplay between tyrosine phosphorylation and dephosphorylation in controlling gene transcription and protein localization.