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Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

Science  26 Jun 2009:
Vol. 324, Issue 5935, pp. 1713-1716
DOI: 10.1126/science.1171721

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Ras, STAT3, and Transformation

The STAT (signal transducer and activator of transcription) proteins are activated in response to receptor stimulation and act in the nucleus to regulate gene expression. Gough et al. (p. 1713) found that STAT3 functioned in transformation of cells by the oncogene Ras. However, this activity was maintained in mutants of STAT that fail to activate transcription. Instead, the active STAT3 appeared to be associated with mitochondria. Furthermore, modified STAT3 targeted to the mitochondria promoted transformation by Ras, and mitochondrial function was disrupted in Ras-transformed cells lacking STAT3. Such transformation-specific effects of STAT3 could be a useful target in developing anticancer therapies.

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.

  • * These authors contributed equally to this work.

  • Present address: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, Prague 4, Czech Republic 14220.

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

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