Nuclear export signal located within the DNA-binding domain of the STAT1 transcription factor

Latent signal transducers and activators of transcription (STATs) reside in the cytoplasm but rapidly accumulate in the nucleus following cytokine sti mulation. Nuclear accumulation requires specific tyrosine phosphorylation a nd STAT dimerization. The presence of STATs in the nucleus is transient, ho wever, and within hours the STATs reappear in the cytoplasm. Results indica te that STAT1 can be dephosphorylated in the nucleus and actively exported by the chromosome region maintenance 1 (CRM1) export receptor. CRM1 recogni zes a specific amino acid sequence located within the DNA-binding domain of STAT1. This region shares sequence and functional properties of characteri zed nuclear export signals. The location of this sequence within STAT1 sugg ests that it is not accessible to CRM1 when STAT1 is bound to DNA. Evidence is presented to support a model in which STAT1 is tyrosine dephosphorylate d in the nucleus and dissociates from DNA, allowing recognition by CRM1 and nuclear export. The regulated export of STAT1 may contribute to silencing of the signal pathway and/or to re-establish STAT1 in the cytoplasm to moni tor activity of receptor-kinase signals.