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. Fidler; Mien Chie Hung

doi:10.1126/scisignal.2000590

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

Department of Oncology

Research output: Contribution to journal › Article › peer-review

94 Citations (Scopus)

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 language	English
Pages (from-to)	ra9
Journal	Science Signaling
Volume	3
Issue number	108
DOIs	https://doi.org/10.1126/scisignal.2000590
Publication status	Published - 2010 Feb 9

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Biology
Cell Biology

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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

@article{ec19780ee25b4561b9c62ebafa4bad21,

title = "ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway",

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.",

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

year = "2010",

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doi = "10.1126/scisignal.2000590",

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Kuo, HP, Lee, DF, Chen, CT, Liu, M, Chou, CK, Lee, HJ, Du, Y, Xie, X, Wei, Y, Xia, W, Weihua, Z, Yang, JY, Yen, CJ, Huang, TH, Tan, M, Xing, G, Zhao, Y, Lin, CH, Tsai, SF, Fidler, IJ & Hung, MC 2010, 'ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway', Science Signaling, vol. 3, no. 108, pp. ra9. https://doi.org/10.1126/scisignal.2000590

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AU - Kuo, Hsu Ping

AU - Lee, Dung Fang

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AU - Lee, Hong Jen

AU - Du, Yi

AU - Xie, Xiaoming

AU - Wei, Yongkun

AU - Xia, Weiya

AU - Weihua, Zhang

AU - Yang, Jer Yen

AU - Yen, Chia Jui

AU - Huang, Tzu Hsuan

AU - Tan, Minjia

AU - Xing, Gang

AU - Zhao, Yingming

AU - Lin, Chien Hsing

AU - Tsai, Shih Feng

AU - Fidler, Isaiah J.

AU - Hung, Mien Chie

PY - 2010/2/9

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N2 - 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.

AB - 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.

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ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway

Abstract

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