Signal transducers and activators of transcription (STATs) were first identified as key signaling molecules in response to
cytokines. Constitutive STAT activation also has been widely implicated in
oncogenesis. We analyzed STAT5-associated
proteins in a leukemic T cell line LSTRA, which exhibits constitutive
tyrosine phosphorylation and activation of STAT5. A cellular
protein was found to specifically interact with STAT5 in LSTRA cells by co-immunoprecipitation. Sequencing analysis and subsequent immunoblotting confirmed the identity of this STAT5-associated
protein as the E2 component of mitochondrial
pyruvate dehydrogenase complex (PDC-E2). Consistent with this interaction, both subcellular fractionation and immunofluorescence microscopy revealed mitochondrial localization of STAT5 in LSTRA cells. Mitochondrial localization of
tyrosine-phosphorylated STAT5 also occurred in
cytokine-stimulated cells. A time course experiment further demonstrated the transient kinetics of STAT5 mitochondrial translocation after
cytokine stimulation. In contrast,
cytokine-induced STAT1 and STAT3 activation did not result in their translocation into mitochondria. Furthermore, we showed that mitochondrial STAT5 bound to the D-loop regulatory region of
mitochondrial DNA in vitro. It suggests a potential role of STAT5 in regulating the mitochondrial genome. Proliferative metabolism toward aerobic glycolysis is well known in
cancer cells as the Warburg effect and is also observed in
cytokine-stimulated cells. Our novel findings of
cytokine-induced STAT5 translocation into mitochondria and its link to
oncogenesis provide important insights into the underlying mechanisms of this characteristic metabolic shift.