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Science 324 (5935): 1713-1716

Copyright © 2009 by the American Association for the Advancement of Science

Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

Daniel J. Gough,1,* Alicia Corlett,1,*,{dagger} Karni Schlessinger,1,{ddagger} Joanna Wegrzyn,2 Andrew C. Larner,2 David E. Levy1,§

Abstract: Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor responsive to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when it is tyrosine-phosphorylated. We report that malignant transformation by activated Ras is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.

1 Department of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
2 Department of Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

* These authors contributed equally to this work.

{dagger} Present address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídenská 1083, Prague 4, Czech Republic 14220.

{ddagger} Present address: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

§ To whom correspondence should be addressed. E-mail: david.levy{at}

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