Article

ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway.

1Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Science Signaling (impact factor: 7.5). 01/2010; 3(108):ra9. DOI:10.1126/scisignal.2000590 pp.ra9
Source: PubMed

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.

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Keywords

allelic loss
 
ARD1
 
ARD1 functions
 
ARD1 inhibits cell proliferation
 
ARD1-TSC2-mTOR axis
 
arrest-defective protein 1
 
breast cancer cell lines
 
heterozygosity
 
inhibitor
 
Mammalian target
 
multiple tumor types
 
rapamycin
 
repressing mTOR activity
 
TSC1)-TSC2 complex
 
TSC2 abundance
 
tuberous sclerosis 1