Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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}med.nyu.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
MCJ/DnaJC15, an Endogenous Mitochondrial Repressor of the Respiratory Chain That Controls Metabolic Alterations.
K. M. Hatle, P. Gummadidala, N. Navasa, E. Bernardo, J. Dodge, B. Silverstrim, K. Fortner, E. Burg, B. T. Suratt, J. Hammer, et al. (2013)
Mol. Cell. Biol. 33, 2302-2314
   Abstract »    Full Text »    PDF »
Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation.
X. Deschenes-Simard, M.-F. Gaumont-Leclerc, V. Bourdeau, F. Lessard, O. Moiseeva, V. Forest, S. Igelmann, F. A. Mallette, M. K. Saba-El-Leil, S. Meloche, et al. (2013)
Genes & Dev. 27, 900-915
   Abstract »    Full Text »    PDF »
Tumor-derived Mutations in the Gene Associated with Retinoid Interferon-induced Mortality (GRIM-19) Disrupt Its Anti-signal Transducer and Activator of Transcription 3 (STAT3) Activity and Promote Oncogenesis.
S. C. Nallar, S. Kalakonda, D. J. Lindner, R. R. Lorenz, E. Lamarre, X. Weihua, and D. V. Kalvakolanu (2013)
J. Biol. Chem. 288, 7930-7941
   Abstract »    Full Text »    PDF »
Cyclophilin D Extramitochondrial Signaling Controls Cell Cycle Progression and Chemokine-directed Cell Motility.
M. Tavecchio, S. Lisanti, A. Lam, J. C. Ghosh, N. M. Martin, M. O'Connell, A. T. Weeraratna, A. V. Kossenkov, L. C. Showe, and D. C. Altieri (2013)
J. Biol. Chem. 288, 5553-5561
   Abstract »    Full Text »    PDF »
The Import of the Transcription Factor STAT3 into Mitochondria Depends on GRIM-19, a Component of the Electron Transport Chain.
P. Tammineni, C. Anugula, F. Mohammed, M. Anjaneyulu, A. C. Larner, and N. B. V. Sepuri (2013)
J. Biol. Chem. 288, 4723-4732
   Abstract »    Full Text »    PDF »
Definitive evidence using enucleated cytoplasts for a nongenomic basis for the cystic change in endoplasmic reticulum structure caused by STAT5a/b siRNAs.
J. E. Lee, Y.-M. Yang, H. Yuan, and P. B. Sehgal (2013)
Am J Physiol Cell Physiol 304, C312-C323
   Abstract »    Full Text »    PDF »
Oncrasin targets the JNK-NF-{kappa}B axis to sensitize glioma cells to TNF{alpha}-induced apoptosis.
P. Gupta, D. Dixit, and E. Sen (2013)
Carcinogenesis 34, 388-396
   Abstract »    Full Text »    PDF »
Mouse hematopoietic cell-targeted STAT3 deletion: stem/progenitor cell defects, mitochondrial dysfunction, ROS overproduction, and a rapid aging-like phenotype.
C. Mantel, S. Messina-Graham, A. Moh, S. Cooper, G. Hangoc, X.-Y. Fu, and H. E. Broxmeyer (2012)
Blood 120, 2589-2599
   Abstract »    Full Text »    PDF »
Plumbagin reverses proliferation and resistance to apoptosis in experimental PAH.
A. Courboulin, M. Barrier, T. Perreault, P. Bonnet, V. L. Tremblay, R. Paulin, E. Tremblay, C. Lambert, M. H. Jacob, S. N. Bonnet, et al. (2012)
Eur. Respir. J. 40, 618-629
   Abstract »    Full Text »    PDF »
STAT3 negatively regulates thyroid tumorigenesis.
J. P. Couto, L. Daly, A. Almeida, J. A. Knauf, J. A. Fagin, M. Sobrinho-Simoes, J. Lima, V. Maximo, P. Soares, D. Lyden, et al. (2012)
PNAS 109, E2361-E2370
   Abstract »    Full Text »    PDF »
JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia.
A. Bonetto, T. Aydogdu, X. Jin, Z. Zhang, R. Zhan, L. Puzis, L. G. Koniaris, and T. A. Zimmers (2012)
Am J Physiol Endocrinol Metab 303, E410-E421
   Abstract »    Full Text »    PDF »
GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis.
N. Shulga and J. G. Pastorino (2012)
J. Cell Sci. 125, 2995-3003
   Abstract »    Full Text »    PDF »
The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia.
R. Kang, T. Loux, D. Tang, N. E. Schapiro, P. Vernon, K. M. Livesey, A. Krasinskas, M. T. Lotze, and H. J. Zeh III (2012)
PNAS 109, 7031-7036
   Abstract »    Full Text »    PDF »
Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies.
P. Sansone and J. Bromberg (2012)
J. Clin. Oncol. 30, 1005-1014
   Abstract »    Full Text »    PDF »
Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function.
J. E. Lee, Y.-M. Yang, F.-X. Liang, D. J. Gough, D. E. Levy, and P. B. Sehgal (2012)
Am J Physiol Cell Physiol 302, C804-C820
   Abstract »    Full Text »    PDF »
Cytokine Signaling: Birth of a Pathway.
J. J. O'Shea, M. Gadina, and Y. Kanno (2011)
J. Immunol. 187, 5475-5478
   Full Text »    PDF »
STAT3 Is Necessary for Proliferation and Survival in Colon Cancer-Initiating Cells.
L. Lin, A. Liu, Z. Peng, H.-J. Lin, P.-K. Li, C. Li, and J. Lin (2011)
Cancer Res. 71, 7226-7237
   Abstract »    Full Text »    PDF »
Identification of Tumorigenic Cells in KrasG12D-Induced Lung Adenocarcinoma.
H.-C. Cho, C.-Y. Lai, L.-E. Shao, and J. Yu (2011)
Cancer Res. 71, 7250-7258
   Abstract »    Full Text »    PDF »
Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms.
S. K.- J. Landor, A. P. Mutvei, V. Mamaeva, S. Jin, M. Busk, R. Borra, T. J. Gronroos, P. Kronqvist, U. Lendahl, and C. M. Sahlgren (2011)
PNAS 108, 18814-18819
   Abstract »    Full Text »    PDF »
Dehydroepiandrosterone inhibits the Src/STAT3 constitutive activation in pulmonary arterial hypertension.
R. Paulin, J. Meloche, M. H. Jacob, M. Bisserier, A. Courboulin, and S. Bonnet (2011)
Am J Physiol Heart Circ Physiol 301, H1798-H1809
   Abstract »    Full Text »    PDF »
Cross-talk between Phospho-STAT3 and PLC{gamma}1 Plays a Critical Role in Colorectal Tumorigenesis.
P. Zhang, Y. Zhao, X. Zhu, D. Sedwick, X. Zhang, and Z. Wang (2011)
Mol. Cancer Res. 9, 1418-1428
   Abstract »    Full Text »    PDF »
Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism.
A. N. Cvrljevic, D. Akhavan, M. Wu, P. Martinello, F. B. Furnari, A. J. Johnston, D. Guo, L. Pike, W. K. Cavenee, A. M. Scott, et al. (2011)
J. Cell Sci. 124, 2938-2950
   Abstract »    Full Text »    PDF »
STAT3 Negatively Regulates Type I IFN-Mediated Antiviral Response.
W.-B. Wang, D. E. Levy, and C.-K. Lee (2011)
J. Immunol. 187, 2578-2585
   Abstract »    Full Text »    PDF »
H11 Kinase/Heat Shock Protein 22 Deletion Impairs Both Nuclear and Mitochondrial Functions of STAT3 and Accelerates the Transition Into Heart Failure on Cardiac Overload.
H. Qiu, P. Lizano, L. Laure, X. Sui, E. Rashed, J. Y. Park, C. Hong, S. Gao, E. Holle, D. Morin, et al. (2011)
Circulation 124, 406-415
   Abstract »    Full Text »    PDF »
STAT3 Plays a Critical Role in KRAS-Induced Pancreatic Tumorigenesis.
R. B. Corcoran, G. Contino, V. Deshpande, A. Tzatsos, C. Conrad, C. H. Benes, D. E. Levy, J. Settleman, J. A. Engelman, and N. Bardeesy (2011)
Cancer Res. 71, 5020-5029
   Abstract »    Full Text »    PDF »
Negative Regulation of STAT3 Protein-mediated Cellular Respiration by SIRT1 Protein.
M. Bernier, R. K. Paul, A. Martin-Montalvo, M. Scheibye-Knudsen, S. Song, H.-J. He, S. M. Armour, B. P. Hubbard, V. A. Bohr, L. Wang, et al. (2011)
J. Biol. Chem. 286, 19270-19279
   Abstract »    Full Text »    PDF »
Mechanisms of STAT Protein Activation by Oncogenic KIT Mutants in Neoplastic Mast Cells.
A. Chaix, S. Lopez, E. Voisset, L. Gros, P. Dubreuil, and P. De Sepulveda (2011)
J. Biol. Chem. 286, 5956-5966
   Abstract »    Full Text »    PDF »
Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis.
G. Ishdorj, J. B. Johnston, and S. B. Gibson (2010)
Mol. Cancer Ther. 9, 3302-3314
   Abstract »    Full Text »    PDF »
STAT1 Is Required for Redifferentiation during Madin-Darby Canine Kidney Tubulogenesis.
M. Kim, L. E. O'Brien, S.-H. Kwon, and K. E. Mostov (2010)
Mol. Biol. Cell 21, 3926-3933
   Abstract »    Full Text »    PDF »
Modulation of Gene Expression and Tumor Cell Growth by Redox Modification of STAT3.
L. Li, S.-h. Cheung, E. L. Evans, and P. E. Shaw (2010)
Cancer Res. 70, 8222-8232
   Abstract »    Full Text »    PDF »
Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation.
K. Friedbichler, M. A. Kerenyi, B. Kovacic, G. Li, A. Hoelbl, S. Yahiaoui, V. Sexl, E. W. Mullner, S. Fajmann, S. Cerny-Reiterer, et al. (2010)
Blood 116, 1548-1558
   Abstract »    Full Text »    PDF »
Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth.
T. Okamoto, T. Inozume, H. Mitsui, M. Kanzaki, K. Harada, N. Shibagaki, and S. Shimada (2010)
Mol. Cancer Ther. 9, 2333-2343
   Abstract »    Full Text »    PDF »
Stoichiometry of STAT3 and Mitochondrial Proteins: IMPLICATIONS FOR THE REGULATION OF OXIDATIVE PHOSPHORYLATION BY PROTEIN-PROTEIN INTERACTIONS.
D. Phillips, M. J. Reilley, A. M. Aponte, G. Wang, E. Boja, M. Gucek, and R. S. Balaban (2010)
J. Biol. Chem. 285, 23532-23536
   Abstract »    Full Text »    PDF »
Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance.
J. You, Y. Yu, L. Jiang, W. Li, X. Yu, L. Gonzalez, G. Yang, Z. Ke, W. Li, C. Li, et al. (2010)
Mol. Cell. Biol. 30, 1650-1659
   Abstract »    Full Text »    PDF »
Mitochondrial p32 Protein Is a Critical Regulator of Tumor Metabolism via Maintenance of Oxidative Phosphorylation.
V. Fogal, A. D. Richardson, P. P. Karmali, I. E. Scheffler, J. W. Smith, and E. Ruoslahti (2010)
Mol. Cell. Biol. 30, 1303-1318
   Abstract »    Full Text »    PDF »
STAT3 Revs Up the Powerhouse.
N. C. Reich (2009)
Science Signaling 2, pe61
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882