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J. Biol. Chem., Vol. 276, Issue 19, 16447-16455, May 11, 2001
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From the Signal transducers and activators of
transcription (STATs) are latent cytoplasmic transcription factors,
which mediate interferon (IFN), interleukin, and some growth factor and
peptide hormone signaling in cells. IFN stimulation results in tyrosine
phosphorylation, dimerization, and nuclear import of STATs. In response
to IFN-
Arginine/Lysine-rich Structural Element Is Involved in
Interferon-induced Nuclear Import of STATs*
§,
Laboratory of Viral and Molecular
Immunology, Department of Microbiology, National Public Health
Institute and the ¶ Diabetes and Genetic epidemiology Unit,
Department of Epidemiology and Health Promotion National Public Health
Institute, FIN-00300 Helsinki, Finland
stimulation, STAT1 forms homodimers, whereas IFN-
induction results in the formation of STAT1·STAT2 heterodimers, which
assemble with p48 protein in the nucleus. Phosphorylation as such is
not sufficient to target STATs into the nucleus; rather, the
dimerization triggered by phosphorylation is essential. Although
IFN-induced nuclear import of STATs is mediated by the importin/Ran
transport system, no classic nuclear localization signal (NLS) has been
found in STATs. In the three-dimensional structure of STAT1, we
observed a structural arginine/lysine-rich element within the
DNA-binding domain of the molecule. We created a series of point
mutations in these elements of STAT1 and STAT2 and showed by transient
transfection/IFN stimulation assay that this site is essential for the
nuclear import of both STAT1 and STAT2. The results suggest that two
arginine/lysine-rich elements, one in each STAT monomer, are required
for IFN-induced nuclear import of STAT dimers. Import-defective STAT1
and STAT2 proteins were readily phosphorylated and dimerized, but they
functioned as dominant negative molecules inhibiting the nuclear import
of heterologous STAT protein.
*
This study was supported by the Medical Research Council of
the Academy of Finland and by the Sigrid Juselius and the Finnish Cancer Foundations.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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