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MTOR TSC2 (1 - 8 of 8)
PMID: 16027121
Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity.
... of TSC2 and activation of mTOR both ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 16027121

Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity.
Source

The Journal of biological chemistry (9/16/2005)

Abstract

Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. The serine/threonine kinase Akt is an upstream positive regulator of the mammalian target of rapamycin (mTOR). However, the mechanism by which Akt activates mTOR is not fully understood. The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR. Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), which is an activator of TSC2. We show that in Akt1/Akt2 DKO cells AMP/ATP ratio is markedly elevated with concomitant increase in AMPK activity, whereas in cells expressing activated Akt there is a dramatic decrease in AMP/ATP ratio and a decline in AMPK activity. Currently, the Akt-mediated phosphorylation of TSC2 and the inhibition of AMPK-mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR. Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK-mediated phosphorylation of TSC2. We propose that the activation of mTOR by Akt-mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo.

PMID: 16816403
AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha.
... of TSC2 and activation of mTOR and ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 16816403

AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha.
Source

The Journal of biological chemistry (9/15/2006)

Abstract

AKT-independent phosphorylation of TSC2 and activation of mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha. Prostaglandin F2alpha (PGF2alpha) is an important mediator of corpus luteum (CL) regression, although the cellular signaling events that mediate this process have not been clearly identified. It is established that PGF2alpha binds to a G-proteincoupled receptor (GPCR) to stimulate protein kinase C (PKC) and Raf-MEK-Erk signaling in luteal cells. The present experiments were performed to determine whether PGF2alpha stimulates the mammalian target of rapamycin (mTOR) /ribosomal protein S6 kinase 1 (S6K1) signaling pathway in steroidogenic luteal cells. We demonstrate that PGF2alpha treatment results in a timeand concentration-dependent stimulation of the phosphorylation and activation of S6K1. The stimulation of S6K1 in response to PGF2alpha treatment was abolished by the mTOR inhibitor rapamycin. Treatment with PGF2alpha did not increase AKT phosphorylation but increased the phosphorylation of Erk and the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), an upstream regulator of mTOR. The effects of PGF2alpha were mimicked by the PKC activator PMA and inhibited by U0126, a MEK1 inhibitor. The activation of mTOR/S6K1 and putative down stream processes involving the translational apparatus (i.e. 4EBP1 phosphorylation, release of 4EBP1 binding in m (7) G cap binding assays, and the phosphorylation and synthesis of S6) were completely sensitive to treatment with rapamycin, implicating mTOR in the actions of PGF2alpha. Taken together, our data suggest that GPCR activation in response to PGF2alpha stimulates the mTOR pathway which increases the translational machinery in luteal cells. The translation of proteins under the control of mTOR may have implications for luteal development and regression and offer new strategies for therapeutic intervention in PGF2alpha-target tissues.

PMID: 21368289
Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.
... lipopolysaccharide enhanced the ... of TSC2, ... reestablished mTOR activation ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 21368289

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells.
Source

Blood (4/21/2011)

Abstract

Inhibition of mTOR blocks the anti-inflammatory effects of glucocorticoids in myeloid immune cells. A central role for the mammalian target of rapamycin (mTOR) in innate immunity has been recently defined by its ability to limit proinflammatory mediators. Although glucocorticoids (GCs) exert potent anti-inflammatory effects in innate immune cells, it is currently unknown whether the mTOR pathway interferes with GC signaling. Here we show that inhibition of mTOR with rapamycin or Torin1 prevented the anti-inflammatory potency of GC both in human monocytes and myeloid dendritic cells. GCs could not suppress nuclear factor-?B and JNK activation, the expression of proinflammatory cytokines, and the promotion of Th1 responses when mTOR was inhibited. Interestingly, long-term activation of monocytes with lipopolysaccharide enhanced the expression of TSC2, the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished mTOR activation. Renal transplant patients receiving rapamycin but not those receiving calcineurin inhibitors displayed a state of innate immune cell hyper-responsiveness despite the concurrent use of GC. Finally, mTOR inhibition was able to override the healing phenotype of dexamethasone in a murine lipopolysaccharide shock model. Collectively, these data identify a novel link between the glucocorticoid receptor and mTOR in innate immune cells, which is of considerable clinical importance in a variety of disorders, including allogeneic transplantation, autoimmune diseases, and cancer.

PMID: 21886784
Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1.
Activation of mTORC1 by TSC2 ablation ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 21886784

Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1.
Source

PloS one (2011)

Abstract

Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1. [AIM] We previously found that chronic tuberous sclerosis protein 2 (TSC2) deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1) and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (ßTSC2 (-/-)) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. [METHODS] Isolated islets from ßTSC2 (-/-) mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. [RESULTS] Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of ßTSC2 (-/-) mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of ßTSC2 (-/-) mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, ßTSC2 (-/-) mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1. [CONCLUSION] Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.

PMID: 22492229
A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2).
A role of the mammalian target of rapamycin (mTOR) in ... TSC2) ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 22492229

A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2).
Source

Journal of molecular neuroscience : MN (June 2012)

Abstract

A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2). Mammalian target of rapamycin (mTOR) signaling plays a critical role in the regulation of activity-dependent protein synthesis in neurons. It is well established that the GTPase-activating protein tuberous sclerosis complex proteins (2TSC2) is an upstream inhibitor of mTOR. In this study, we show that glutamate stimulation down-regulates TSC2 protein in cortical cultures via NMDA receptor (NMDAR) activation. Interestingly, the mTOR-specific inhibitor rapamycin blocks the glutamate-induced TSC2 down-regulation. This finding suggests that NMDAR activation evokes an mTOR-mediated negative regulation of TSC2. In addition, we also show that the glutamate-induced down-regulation of TSC2 protein is blocked by proteasome inhibitor MG132, indicating the involvement of proteasome-mediated protein degradation. We propose that the NMDAR activation stimulates an mTOR-proteasome pathway to degrade TSC2 protein.

... an mTOR-mediated negative ... of TSC2.   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 22492229

A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2).
Source

Journal of molecular neuroscience : MN (June 2012)

Abstract

A role of the mammalian target of rapamycin (mTOR) in glutamate-induced down-regulation of tuberous sclerosis complex proteins 2 (TSC2). Mammalian target of rapamycin (mTOR) signaling plays a critical role in the regulation of activity-dependent protein synthesis in neurons. It is well established that the GTPase-activating protein tuberous sclerosis complex proteins (2TSC2) is an upstream inhibitor of mTOR. In this study, we show that glutamate stimulation down-regulates TSC2 protein in cortical cultures via NMDA receptor (NMDAR) activation. Interestingly, the mTOR-specific inhibitor rapamycin blocks the glutamate-induced TSC2 down-regulation. This finding suggests that NMDAR activation evokes an mTOR-mediated negative regulation of TSC2. In addition, we also show that the glutamate-induced down-regulation of TSC2 protein is blocked by proteasome inhibitor MG132, indicating the involvement of proteasome-mediated protein degradation. We propose that the NMDAR activation stimulates an mTOR-proteasome pathway to degrade TSC2 protein.

PMID: 22737271
Regulation of PI 3-K, PTEN, p53, and mTOR in Malignant and Benign Tumors Deficient in Tuberin.
... of TSC-2, ... as activation of ... and mTOR is ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 22737271

Regulation of PI 3-K, PTEN, p53, and mTOR in Malignant and Benign Tumors Deficient in Tuberin.
Source

Genes & cancer (November 2011)

Abstract

Regulation of PI 3-K, PTEN, p53, and mTOR in Malignant and Benign Tumors Deficient in Tuberin. The tuberous sclerosis complex (TSC) is caused by mutation in either of 2 tumor suppressor genes, TSC-1 (encodes hamartin) and TSC-2 (encodes tuberin). In humans, deficiency in TSC1/2 is associated with benign tumors in many organs, including renal angiomyolipoma (AML) but rarely renal cell carcinoma (RCC). In contrast, deficiency of TSC function in the Eker rat is associated with RCC. Here, we have investigated the activity of PI 3-K and the expression of PTEN, p53, tuberin, p-mTOR, and p-p70S6K in both Eker rat RCC and human renal AML. Compared to normal tissue, increased PI 3-K activity was detected in RCC of Eker rats but not in human AML tissue. In contrast, PTEN was highly expressed in AML but significantly reduced in the renal tumors of Eker rats. Phosphorylation on Ser (2448) of mTOR and Thr (389) of p70S6K were significantly increased in both RCC and AML compared to matching control tissue. Total tuberin was significantly decreased in AML while completely lost in RCC of Eker rats. Our data also show that while p53 protein expression is lost in rat RCC, it was highly elevated in AML. These novel data provide evidence that loss of TSC-2, PTEN, and p53 as well as activation of PI 3-K and mTOR is associated with kidney cancer in the Eker rat, while sustained expression of TSC-2, PTEN, and p53 may prevent progression of kidney cancer in TSC patients.

PMID: 23800068
Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1?
... suppressing mTORC2-mediated Akt/TSC2 signalling ...   (details)

MTOR TSC2

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MLST8   RICTOR   MTOR )

PMID: 23800068

Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1?
Source

Experimental dermatology (July 2013)

Abstract

Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFa signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKß-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.