Abstract #LB-183: Mitochondrial translocation of STAT5 in leukemic T cells and cytokine-stimulated cells
Authors: Fu-Yu Chueh, Chao-Lan Yu
Journal: Cancer Research (2009)

Signal transducers and activators of transcription (STATs) were first identified as key signaling molecules in response to cytokines. Tyrosine-phosphorylated active STATs translocate to the nucleus and regulate genes important in controlling cell proliferation, resistance to apoptosis, angiogenesis, and immune evasion. We and others have shown that STAT proteins, mostly STAT3 and STAT5a/b, are constitutively active in a wide variety of tumor cells. These findings point to the critical role of STAT activation in oncogenesis. To further elucidate the underlying mechanisms, we analyzed STAT-associated proteins in a leukemic T cell line LSTRA that exhibits constitutive STAT5 activation. A cellular protein was found to specifically interact with STAT5 in LSTRA cells by coimmunoprecipitation. Sequencing analyses revealed the identity of this STAT5-associated protein as the E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2). Subcellular fractionation experiments were conducted to isolate mitochondria-enriched heavy membrane fractions. We found that, indeed, tyrosine-phosphorylated STAT5a/b are present in mitochondria of LSTRA cells. To explore the possibility of cytokine-induced STAT5 translocation into mitochondria, we examined IL-2-dependent CTLL-20 and IL-3-dependent BaF3 cells before and after cytokine stimulation. Subcellular fractionation studies showed the presence of tyrosine-phosphorylated STAT5 in mitochondria only after cytokine stimulation. Interestingly, IFN-\#947;-induced STAT1 activation and IL-2-induced STAT3 activation did not result in their translocation into mitochondria. A time course experiment further demonstrated the transient kinetics of STAT5 mitochondrial translocation that peaks at 15 minutes after cytokine stimulation. More importantly, mitochondrial STAT5 induced by cytokine stimulation binds DNA in a gel shift assay suggesting a potential role of STAT5 in modulating mitochondrial DNA expression. We cannot exclude the possibility that STAT5 may have other functions in mitochondria. This hypothesis is supported by a recent report demonstrating a role of mitochondrial STAT3 in the activities of complexes I and II of the electron transport chain in mouse cells (Science 323:793, 2009). PDC are the key enzymes in mitochondria that convert pyruvate into acetyl-CoA to be used in the citric acid cycle for cellular respiration. The interaction between STAT5 and PDC-E2 suggests a potential role of STAT5 in regulating energy production in mitochondria. Its constitutive mitochondrial localization in tumor cells, therefore, may aid in the higher metabolic rate commonly observed in cancer. Our novel findings represent the first report of cytokine-induced STAT5 translocation into mitochondria in human and mouse cells as well as its link to oncogenesis. Experiments are in progress to further elucidate the functions of mitochondrial STAT5.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-183.