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PNAS 97 (19): 10418-10423

Copyright © 2000 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain

Andreas Begitt*,{dagger}, Thomas Meyer*,{dagger}, Marleen van Rossum*, and Uwe Vinkemeier*,{dagger},{ddagger}

*Nachwuchsgruppe Zelluläre Signalverarbeitung, Forschungsinstitut für Molekulare Pharmakologie, and {dagger}Freie Universität, Institut für Kristallographie, D-10315 Berlin, Germany

Accepted for publication July 10, 2000.

Received for publication March 24, 2000.

Abstract: Signal transducer and activator of transcription (Stat) proteins are latent transcription factors that reside in the cytoplasm before activation. On cytokine-induced tyrosine phosphorylation, these molecules dimerize and accumulate transiently in the nucleus. No specific signals mediating these processes have been identified to date. In this report, we examine the nuclear export of Stat1. We find that treatment of cells with the export inhibitor leptomycin B does not affect steady-state localization of Stat1 but impedes nuclear export after IFN{gamma}-induced nuclear accumulation. We identify a conserved leucine-rich helical segment in the coiled-coil domain of Stat1, which is responsible for the efficient nuclear export of this protein. Mutation of two hallmark leucines within this segment greatly attenuate the back transport of Stat1 in the cytoplasm. When fused to a carrier protein, the Stat1 export sequence can mediate nuclear export after intranuclear microinjection. We show that prolonging the nuclear presence of Stat1 by inhibiting nuclear export reduces the transcriptional response to stimulation with IFN{gamma}. These data suggest that Stats are actively exported from the nucleus via several separate pathways and link this activity to transcriptional activation.


{ddagger} To whom reprint requests should be addressed at: Nachwuchsgruppe Zelluläre Signalverarbeitung, Forschungsinstitut für Molekulare Pharmakologie, Alfred-Kowalke-Strasse-4, D-10315 Berlin. E-mail: vinkemeier{at}fmp-berlin.de.

Communicated by James E. Darnell, Jr., The Rockefeller University, New York, NY

Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.190318397.

Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.190318397

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