Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

被引:626
作者
Gough, Daniel J. [1 ,2 ]
Corlett, Alicia [1 ,2 ]
Schlessinger, Karni [1 ,2 ]
Wegrzyn, Joanna [3 ,4 ]
Larner, Andrew C. [3 ,4 ]
Levy, David E. [1 ,2 ]
机构
[1] New York Univ, Sch Med, Dept Pathol, New York, NY 10016 USA
[2] New York Univ, Sch Med, Inst Canc, New York, NY 10016 USA
[3] Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA
[4] Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23298 USA
关键词
SIGNAL TRANSDUCER; GENE; ACTIVATION; PROTEIN; PHOSPHORYLATION; INTERLEUKIN-6; INTERFERONS; CYTOKINES; TARGET; CANCER;
D O I
10.1126/science.1171721
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];
摘要
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.
引用
收藏
页码:1713 / 1716
页数:4
相关论文
共 24 条
[1]
MOLECULAR-CLONING OF APRF, A NOVEL IFN-STIMULATED GENE FACTOR-3 P91-RELATED TRANSCRIPTION FACTOR INVOLVED IN THE GP130-MEDIATED SIGNALING PATHWAY [J].
AKIRA, S ;
NISHIO, Y ;
INOUE, M ;
WANG, XJ ;
WEI, S ;
MATSUSAKA, T ;
YOSHIDA, K ;
SUDO, T ;
NARUTO, M ;
KISHIMOTO, T .
CELL, 1994, 77 (01) :63-71
[2]
Stat3 as an oncogene [J].
Bromberg, JF ;
Wrzeszczynska, MH ;
Devgan, G ;
Zhao, YX ;
Pestell, RG ;
Albanese, C ;
Darnell, JE .
CELL, 1999, 98 (03) :295-303
[3]
Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target [J].
Chiarle, R ;
Simmons, WJ ;
Cai, HY ;
Dhall, G ;
Zamo', A ;
Raz, R ;
Karras, JG ;
Levy, DE ;
Inghirami, G .
NATURE MEDICINE, 2005, 11 (06) :623-629
[4]
Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance [J].
Fantin, Valeria R. ;
St-Pierre, Julie ;
Leder, Philip .
CANCER CELL, 2006, 9 (06) :425-434
[5]
Gao S.P., 2006, SCI STKE, V2006, ppe30
[6]
Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas [J].
Gao, Sizhi Paul ;
Mark, Kevin G. ;
Leslie, Kenneth ;
Pao, William ;
Motoi, Noriko ;
Gerald, William L. ;
Travis, William D. ;
Bornmann, William ;
Veach, Darren ;
Clarkson, Bayard ;
Bromberg, Jacqueline F. .
JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (12) :3846-3856
[7]
New and old functions of STAT3 - A pivotal target for individualized treatment of cancer [J].
Inghirami, G ;
Chiarle, R ;
Simmons, WJ ;
Piva, R ;
Schlessinger, K ;
Levy, DE .
CELL CYCLE, 2005, 4 (09) :1131-1133
[8]
STATs: Transcriptional control and biological impact [J].
Levy, DE ;
Darnell, JE .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2002, 3 (09) :651-662
[9]
What does Stat3 do? [J].
Levy, DE ;
Lee, CK .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 109 (09) :1143-1148
[10]
Fluorescence protease protection of GFP chimeras to reveal protein topology and subcellular localization [J].
Lorenz, H ;
Hailey, DW ;
Lippincott-Schwartz, J .
NATURE METHODS, 2006, 3 (03) :205-210