ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway

Hsu Ping Kuo, Dung Fang Lee, Chun Te Chen, Mo Liu, Chao Kai Chou, Hong Jen Lee, Yi Du, Xiaoming Xie, Yongkun Wei, Weiya Xia, Zhang Weihua, Jer Yen Yang, Chia Jui Yen, Tzu Hsuan Huang, Minjia Tan, Gang Xing, Yingming Zhao, Chien Hsing Lin, Shih Feng Tsai, Isaiah J. FidlerMien Chie Hung

Research output: Contribution to journalArticle

74 Scopus citations

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 arrestdefective 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.

Original languageEnglish (US)
Pages (from-to)ra9
JournalScience signaling
Volume3
Issue number108
DOIs
StatePublished - Feb 9 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Kuo, H. P., Lee, D. F., Chen, C. T., Liu, M., Chou, C. K., Lee, H. J., Du, Y., Xie, X., Wei, Y., Xia, W., Weihua, Z., Yang, J. Y., Yen, C. J., Huang, T. H., Tan, M., Xing, G., Zhao, Y., Lin, C. H., Tsai, S. F., ... Hung, M. C. (2010). ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Science signaling, 3(108), ra9. https://doi.org/10.1126/scisignal.2000590