ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway.
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.
1Department of Molecular and Cellular Oncology, Unit 108, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Hsu-Ping
HP
Kuo
Dung-Fang
DF
Lee
Chun-Te
CT
Chen
Mo
M
Liu
Chao-Kai
CK
Chou
Hong-Jen
HJ
Lee
Yi
Y
Du
Xiaoming
X
Xie
Yongkun
Y
Wei
Weiya
W
Xia
Zhang
Z
Weihua
Jer-Yen
JY
Yang
Chia-Jui
CJ
Yen
Tzu-Hsuan
TH
Huang
Minjia
M
Tan
Gang
G
Xing
Yingming
Y
Zhao
Chien-Hsing
CH
Lin
Shih-Feng
SF
Tsai
Isaiah J
IJ
Fidler
Mien-Chie
MC
Hung
D000123:Acetyltransferases / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D051379:Mice; D063209:N-Terminal Acetyltransferase A; D063213:N-Terminal Acetyltransferase E; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D034741:RNA, Small Interfering; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000123:Acetyltransferases; D063209:N-Terminal Acetyltransferase A; C504824:NAA10 protein, human; D063213:N-Terminal Acetyltransferase E