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Sci. Signal., 9 February 2010
Vol. 3, Issue 108, p. ra9
[DOI: 10.1126/scisignal.2000590]


ARD1 Stabilization of TSC2 Suppresses Tumorigenesis Through the mTOR Signaling Pathway

Hsu-Ping Kuo1,2, Dung-Fang Lee1,2, Chun-Te Chen1,2, Mo Liu1,2, Chao-Kai Chou1,2, Hong-Jen Lee1,2, Yi Du1,2, Xiaoming Xie1,3, Yongkun Wei1, Weiya Xia1, Zhang Weihua4, Jer-Yen Yang1,2, Chia-Jui Yen1, Tzu-Hsuan Huang1, Minjia Tan5, Gang Xing6, Yingming Zhao6*, Chien-Hsing Lin7, Shih-Feng Tsai7, Isaiah J. Fidler2,4, and Mien-Chie Hung1,2,8,9{dagger}

1 Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
2 Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
3 Department of Breast Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510275, China.
4 Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
5 Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
6 Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7 Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan.
8 Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University and Hospital, Taichung 404, Taiwan.
9 Asia University, Taichung 413, Taiwan.

* Present address: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.

Abstract: Mammalian target of rapamycin (mTOR) regulates various cellular functions, including tumorigenesis, and is inhibited by the tuberous sclerosis 1 (TSC1)–TSC2 complex. Here, we demonstrate that arrest-defective protein 1 (ARD1) physically interacts with, acetylates, and stabilizes TSC2, thereby repressing mTOR activity. The inhibition of mTOR by ARD1 inhibits cell proliferation and increases autophagy, thereby inhibiting tumorigenicity. Correlation between ARD1 and TSC2 abundance was apparent in multiple tumor types. Moreover, evaluation of loss of heterozygosity at Xq28 revealed allelic loss in 31% of tested breast cancer cell lines and tumor samples. Together, our findings suggest that ARD1 functions as an inhibitor of the mTOR pathway and that dysregulation of the ARD1-TSC2-mTOR axis may contribute to cancer development.

{dagger} To whom correspondence should be addressed. E-mail: mhung{at}

Citation: H.-P. Kuo, D.-F. Lee, C.-T. Chen, M. Liu, C.-K. Chou, H.-J. Lee, Y. Du, X. Xie, Y. Wei, W. Xia, Z. Weihua, J.-Y. Yang, C.-J. Yen, T.-H. Huang, M. Tan, G. Xing, Y. Zhao, C.-H. Lin, S.-F. Tsai, I. J. Fidler, M.-C. Hung, ARD1 Stabilization of TSC2 Suppresses Tumorigenesis Through the mTOR Signaling Pathway. Sci. Signal. 3, ra9 (2010).

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