STAT3 is a latent cytoplasmic transcription factor responsive to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when 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, are retained in the cytoplasm, or 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.
Interferons (IFNs) were discovered nearly 60 years ago as a family of cytokines induced during and protecting from viral infection. They have been documented to play essential roles in numerous physiological processes beyond innate antiviral defense, including immunomodulation, regulation of the cell cycle, cell survival and differentiation, and the host response to microbial pathogens. Recent data have also uncovered a potentially darker side to the functions of IFN, including roles in autoimmunity and diabetes. Many IFN effects occur in the absence of acute viral infection, highlighting a physiologic role for constitutively produced IFN. Type I IFNs are constitutively produced at vanishingly low quantities and yet exert profound effects, mediated at least in part through modulation of signaling intermediates required for diverse cytokine response pathways. We review evidence for a yin-yang of IFN function through its role in modulating crosstalk between multiple cytokines by both feed-forward and feed-back regulation of common signaling intermediates and postulate that a similar mechanism underlies a homeostatic role for IFN through tonic signaling in the absence of acute infection.
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