title: TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1.
abstract: The mammalian target of rapamycin (mTOR) is a highly conserved serine-threonine kinase activated in response to growth factors and nutrients. Because of frequent dysregulation of the mTOR signaling pathway in diverse human cancers, this kinase is a key therapeutic target. Redd1 is a negative regulator of mTOR, mediating dissociation of 14-3-3 from tuberous sclerosis complex (TSC)2, which allows formation of a TSC-TSC2 complex. In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein. Redd1 and TXNIP expression was induced by a synthetic glucose analog, 2-deoxyglucose (2-DG). Moreover, Redd1 expression in response to 2-DG was regulated by activating transcription factor 4 (ATF4). Overexpression of TXNIP was associated with reduced mTOR activity mediated by an increase in Redd1 level, whereas knockdown of TXNIP using small interfering RNA resulted in recovery of mTOR activity via downregulation of Redd1 during treatment with 2-DG. Interestingly, Redd1 was additionally stabilized via interactions with N-terminal-truncated TXNIP, leading to suppression of mTOR activity. Our results collectively demonstrate that TXNIP stabilizes Redd1 protein induced by ATF4 in response to 2-DG, resulting in potentiation of mTOR suppression. To the best of our knowledge, this is the first study to identify TXNIP as a novel member of the mTOR upstream that acts as a negative regulator in response to stress signals.
authors: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul. hyeonok@kirams.re.kr
authors: H-O
authors: HO
authors: Jin
authors: S-K
authors: SK
authors: Seo
authors: Y-S
authors: YS
authors: Kim
authors: S-H
authors: SH
authors: Woo
authors: K-H
authors: KH
authors: Lee
authors: J-Y
authors: JY
authors: Yi
authors: S-J
authors: SJ
authors: Lee
authors: T-B
authors: TB
authors: Choe
authors: J-H
authors: JH
authors: Lee
authors: S
authors: S
authors: An
authors: S-I
authors: SI
authors: Hong
authors: I-C
authors: IC
authors: Park
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology; D006801:Humans; D055550:Protein Stability; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D002352:Carrier Proteins; C469991:DDIT4 protein, human; C486715:TXNIP protein, human; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D003847:Deoxyglucose; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases