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First published online 28 August 2007
doi: 10.1242/jcs.03482

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Nucleocytoplasmic shuttling of persistently activated STAT3

Andreas Herrmann^1,*,, Michael Vogt^1,*, Martin Mönnigmann^2,, Thomas Clahsen¹, Ulrike Sommer¹, Serge Haan¹, Valeria Poli³, Peter C. Heinrich¹ and Gerhard Müller-Newen^1,¶

¹ Institut für Biochemie, Universitätsklinikum RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
² Lehrstuhl für Prozesstechnik, RWTH Aachen, Templergraben 55, 52056 Aachen, Germany
³ Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Torino, Italy

^¶ Author for correspondence (e-mail: mueller-newen{at}rwth-aachen.de)

Accepted 5 July 2007

Persistent activation of the transcription factor STAT3 has been detected in many types of cancer and plays an important role in tumor progression, immune evasion and metastasis. To analyze persistent STAT3 activation we coexpressed STAT3 with v-Src. We found that tyrosine phosphorylation of STAT3 by v-Src is independent of Janus kinases (Jaks), the canonical activators of STATs. The STAT3-induced feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), did not interfere with STAT3 activation by v-Src. However, the protein inhibitor of activated STAT3 (PIAS3) suppressed gene induction by persistently activated STAT3. We measured nucleocytoplasmic shuttling of STAT3 in single cells by bleaching the YFP moiety of double-labelled STAT3-CFP-YFP in the cytoplasm. Analysis of the subcellular distribution of CFP and YFP fluorescence over time by mathematical modeling and computational parameter estimation revealed that activated STAT3 shuttles more rapidly than non-activated STAT3. Inhibition of exportin-1-mediated nuclear export slowed down nucleocytoplasmic shuttling of v-Src-activated STAT3 resulting in reduced tyrosine phosphorylation, decreased induction of STAT3 target genes and increased apoptosis. We propose passage of persistently activated STAT3 through the nuclear pore complex as a new target for intervention in cancer.

Key words: STAT3, v-Src, iFLAP, Nucleocytoplasmic shuttling, Apoptosis, Cancer

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