A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis

被引:31
作者
Link, Jason M. [1 ]
Ota, Sara [1 ]
Zhou, Zi-Qiang [1 ]
Daniel, Colin J. [2 ]
Sears, Rosalie C. [2 ,4 ]
Hurlin, Peter J. [1 ,3 ,4 ]
机构
[1] Shriners Hosp Children Portland, Portland, OR 97239 USA
[2] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA
[3] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA
[4] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97239 USA
基金
美国国家卫生研究院;
关键词
cancer; antioxidant; buthionine sulfoximine; Ras; Bcl-2; MAX-INTERACTING PROTEIN; C-MYC; IN-VIVO; TRANSCRIPTIONAL REPRESSOR; ENERGY-METABOLISM; ANTAGONIST MNT; CYCLE ENTRY; APOPTOSIS; GROWTH; ACTIVATION;
D O I
10.1073/pnas.1206406109
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
07 ; 0710 ; 09 ;
摘要
Mnt (Max's next tango) is a Max-interacting transcriptional repressor that can antagonize both the proproliferative and proapoptotic functions of Myc in vitro. To ascertain the physiologically relevant functions of Mnt and to help define the relationship between Mnt and Myc in vivo, we generated a series of mouse strains in which Mnt was deleted in T cells in the absence of endogenous c-Myc or in the presence of ectopic c-Myc. We found that apoptosis caused by loss of Mnt did not require Myc but that ectopic Myc expression dramatically decreased the survival of both Mnt-deficient T cells in vivo and Mnt-deficient MEFs in vitro. Consequently, Myc-driven proliferative expansion of T cells in vitro and thymoma formation in vivo were prevented by the absence of Mnt. Consistent with T-cell models, mouse embryo fibroblasts (MEFs) lacking Mnt were refractory to oncogenic transformation by Myc. Tumor suppression caused by loss of Mnt was linked to increased apoptosis mediated by reactive oxygen species (ROS). Thus, although theoretically and experimentally a Myc antagonist, the dominant physiological role of Mnt appears to be suppression of apoptosis. Our results redefine the physiological relationship between Mnt and Myc and requirements for Myc-driven oncogenesis.
引用
收藏
页码:19685 / 19690
页数:6
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