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Constitutive and IFN‐γ‐induced nuclear import of STAT1 proceed through independent pathways
Author(s) -
Meyer Thomas,
Begitt Andreas,
Lödige Inga,
van Rossum Marleen,
Vinkemeier Uwe
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.3.344
Subject(s) - biology , nuclear transport , signal transduction , microbiology and biotechnology , nuclear protein , genetics , cell nucleus , computational biology , transcription factor , gene
STAT1 functions as both a constitutive transcriptional regulator and, in response to cytokine stimulation of cells, as an inducible tyrosine‐phosphorylated transcription factor. Here, we identify and characterize a non‐transferable nuclear targeting sequence in the STAT1 DNA‐binding domain. This conserved signal is critical for the interferon‐γ (IFN‐γ)‐induced nuclear import of phosphorylated STAT1 dimers and requires adjacent positively charged and hydrophobic residues for functioning. Additionally, the constitutive nucleocytoplasmic shuttling of STAT1 in the absence of IFN‐γ stimulation is revealed. Nuclear import and export of unphosphorylated STAT1 are demonstrated to be sensitive towards wheat germ agglutinin and to occur independently of the import receptor p97. Loss‐of‐function mutations of the dimer‐specific import signal block nuclear entry of tyrosine‐phosphorylated STAT1, which in turn also prevents induction of cytokine‐inducible target genes. Nevertheless, nuclear import of unphosphorylated STAT1 continues and the STAT1‐dependent constitutive expression of caspases and the tumor necrosis factor‐α‐mediated induction of apoptosis proceed unaltered. Thus, tyrosine‐phosphorylated and unphosphorylated STAT1 molecules shuttle via independent pathways to distinct sets of target genes.