The mTOR Pathway Controls Cell Proliferation by Regulating the FoxO3a Transcription Factor via SGK1 Kinase

Mori, Shunsuke; Nada, Shigeyuki; Kimura, Hironobu; Tsuji, Shoji; Takahashi, Yusuke; Kitamura, Ayaka; Oneyama, Chitose; Okada, Masato

doi:10.1371/journal.pone.0088891

Cited by 83 publications

(69 citation statements)

References 55 publications

(76 reference statements)

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“…7 Although Akt can phosphorylate FoxO3a, 16,17 the role of SGK-1 in CKD-induced dephosphorylation of FoxO3a is unknown. In muscles of SGK-1-KO mice with CKD, there is a reduction in phosphorylation of FoxO3a compared with results in WT mice.…”

Section: Sgk-1-ko Increases the Activation Of Foxo3a And Smad2/3mentioning

confidence: 99%

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

Luo

Liang

et al. 2016

JASN

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Muscle proteolysis in CKD is stimulated when the ubiquitin-proteasome system is activated. Serum glucocorticoid-regulated kinase 1 (SGK-1) is involved in skeletal muscle homeostasis, but the role of this protein in CKDinduced muscle wasting is unknown. We found that, compared with muscles from healthy controls, muscles from patients and mice with CKD express low levels of SGK-1. In mice, SGK-1-knockout (SGK-1-KO) induced muscle loss that correlated with increased expression of ubiquitin E3 ligases known to facilitate protein degradation by the ubiquitin-proteasome, and CKD substantially aggravated this response. SGK-1-KO also altered the phosphorylation levels of transcription factors FoxO3a and Smad2/3. In C2C12 muscle cells, expression of dominant negative FoxO3a or knockdown of Smad2/3 suppressed the upregulation of E3 ligases induced by loss of SGK-1. Additionally, SGK-1 overexpression increased the level of phosphorylated N-myc downstreamregulated gene 1 protein, which directly interacted with and suppressed the phosphorylation of Smad2/3. Overexpression of SGK-1 in wild-type mice with CKD had similar effects on the phosphorylation of FoxO3a and Smad2/3 and prevented CKD-induced muscle atrophy. Finally, mechanical stretch of C2C12 muscle cells or treadmill running of wild-type mice with CKD stimulated SGK-1 production, and treadmill running inhibited proteolysis in muscle. These protective responses were absent in SGK-1-KO mice. Thus, SGK-1 could be a mechanical sensor that mediates exercise-induced improvement in muscle wasting stimulated by CKD. 27: 279727: -280827: , 201627: . doi: 10.1681 CKD is frequently complicated by muscle atrophy because of stimulation of muscle protein degradation mediated by increased activity of both caspase-3 and the ubiquitin-proteasome system (UPS). 1 In muscles of rodents with CKD, caspase-3 stimulates cleavage of the complex structure of muscle protein to provide substrates for degradation by the UPS; it also stimulates proteolytic activity of the 26S proteasome. 2 The UPS can selectively degrade myofibrillar protein by stimulating the expression of ubiquitin E3 ligases, Atrogin1 and MuRF1. These ligases conjugate ubiquitin to proteins targeted for protein degradation, resulting in their degradation in the 26S proteasome. 3 Conditions associated with CKD that initiate loss of muscle mass include metabolic acidosis, inflammation, excess angiotensin II, myostatin expression, and insulin resistance. 1 J Am Soc Nephrol

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Section: Sgk-1-ko Increases the Activation Of Foxo3a And Smad2/3mentioning

confidence: 99%

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

Luo

Liang

et al. 2016

JASN

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“…After being activated by growth factors, mTORC2 regulates cell growth and proliferation via phosphorylation of Akt at Ser473 and SGK1. 9 Activation of Akt and SGK1 results in phosphorylation and nuclear export inactivation of the transcription factor FoxO3a, 9,10 which regulates the expression of autophagyrelated genes, such as LC3 and BNIP3. 11,12 In this manner, mTORC2 also acts as a negative regulator of autophagy.…”

Section: Introductionmentioning

confidence: 99%

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

Huang

Qiu

et al. 2015

Cancer Biology & Therapy

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Abbreviations: BAFA1, bafilomycin A1; CPT, Camptothecin; miRNA, microRNA; LC3, microtubule-associated protein 1 light chain 3; mTOR, mechanistic target of rapamycin; Rictor, Rptor independent companion of mTOR complex 2; MUT, mutated; UTR, untranslated region; NC, negative control.It has been reported that persistent or excessive autophagy promotes cancer cell death during chemotherapy, either by enhancing the induction of apoptosis or mediating autophagic cell death. Here, we show that miR-15a and miR-16 are potent inducers of autophagy. Rictor, a component of mTORC2 complex, is directly targeted by miR-15a/16. Overexpression of miR-15a/16 or depletion of endogenous Rictor attenuates the phosphorylation of mTORC1 and p70S6K, inhibits cell proliferation and G1/S cell cycle transition in human cervical carcinoma HeLa cells. Moreover, miR15a/16 dramatically enhances anticancer drug camptothecin (CPT)-induced autophagy and apoptotic cell death in HeLa cells. Collectively, these data demonstrate that miR-15a/16 induced autophagy contribute partly to their inhibition of cell proliferation and enhanced chemotherapeutic efficacy of CPT.

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“…mTOR is a serine/threonine kinase which regulates cellular growth (17, 18). In the nervous system, mTOR signaling functions include modulation of inhibitory synapses onto excitatory neurons (19), synaptic plasticity (20), gliogenesis (21), autophagy (22), and Tau protein homeostasis (23).…”

Section: Introductionmentioning

confidence: 99%

Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia

et al. 2015

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Neuropathology of resected brain tissue has revealed an association of focal cortical dysplasia (FCD) with drug resistant epilepsy (DRE). Recent studies have shown that the mechanistic target of rapamycin (mTOR) pathway is hyperactivated in FCD as evidenced by increased phosphorylation of the ribosomal protein S6 (S6) at serine 240/244 (S240/244), a downstream target of mTOR. Moreover, extracellular regulated kinase (ERK) has been shown to phosphorylate S6 at serine 235/236 (S235/236) and tuberous sclerosis complex 2 (TSC2) at serine 664 (S664) leading to hyperactive mTOR signaling. We evaluated ERK phosphorylation of S6 and TSC2 in two types of FCD (FCD I and FCDII) as a candidate mechanism contributing to mTOR pathway dysregulation in this disorder. Tissue samples from patients with tuberous sclerosis (TS) served as a positive control. Immunostaining for phospho-S6 (pS6240/244 and pS6235/236), phospho-ERK (pERK), and phospho-TSC2 (pTSC2) was performed on resected brain tissue with FCD and TS. We found increased pS6240/244 and pS6235/236 staining in FCD I, FCD II, and TS compared to normal appearing tissue, while pERK and pTSC2 staining was increased only in FCD IIb and TS tissue. Our results suggest that both the ERK and mTOR pathways are dysregulated in FCD and TS; however, the signaling alterations are different for FCD I as compared to FCD II and TS.

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The mTOR Pathway Controls Cell Proliferation by Regulating the FoxO3a Transcription Factor via SGK1 Kinase

Cited by 83 publications

References 55 publications

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

Serum Glucocorticoid–Regulated Kinase 1 Blocks CKD–Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3

MiR-15a and miR-16 induce autophagy and enhance chemosensitivity of Camptothecin

Activation of extracellular regulated kinase and mechanistic target of rapamycin pathway in focal cortical dysplasia

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