scholarly journals Insulin Receptor Substrate-2 Proteasomal Degradation Mediated by a Mammalian Target of Rapamycin (mTOR)-induced Negative Feedback Down-regulates Protein Kinase B-mediated Signaling Pathway in β-Cells

2004 ◽  
Vol 280 (3) ◽  
pp. 2282-2293 ◽  
Author(s):  
Isabelle Briaud ◽  
Lorna M. Dickson ◽  
Melissa K. Lingohr ◽  
Jill F. McCuaig ◽  
John C. Lawrence ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Negative Feedback ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Proteasomal Degradation ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Β Cells

Gambogic Acid Affects Ribosomal Occurrence in Glioma Cells by Downregulating the Phosphoinositide Kinase-3/Protein Kinase B/Mammalian Target of Rapamycin Signaling Pathway

2020 ◽  
Vol 20 (6) ◽  
pp. 3361-3372 ◽  
Author(s):  
Guoxuan Luo ◽  
Shengqiang Jiang ◽  
Xu Zhang ◽  
Yunzhi Ling ◽  
Hengshan Luo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Gambogic Acid ◽  
Mtor Signaling Pathway ◽  
Phosphoinositide Kinase

Gambogic acid (GA) is a natural compound with a polyprenylated xanthone structure that has antiinflammatory, antioxidant, and neuroprotective properties and acts as a chemopreventive agent. GA exhibits anti-tumor, antimicrobial, and anti-proliferative effects on cancer cells. In the current study, the effect of GA on phosphoinositide kinase-3 (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was examined in human U251 glioma cells. Cell viability and apoptosis were evaluated by MTT and Annexin V/PI Double Staining. The expressions of P38, AKT, and mTOR were evaluated by western blot and qRT-PCR, respectively. MagBeads Total RNA Extraction Kit was used to isolate cell tissue RNA. GA decreased the phosphorylation of P38, AKT, and mTOR. Inhibitors of PI3K (LY294002) enhanced the phosphorylation of P38, AKT, and mTOR. GA reduced the phosphorylation of ribosomal protein precursors (Pre) and upstream binding factor (UBF), and insulin-like growth factor I (IGF-1) further enhanced the cell proliferation and expression of Pre and UBF. These results suggested that downregulation of PI3K/AKT/mTOR signaling pathway may be an important mediator in GA-affected ribosomal occurrence in glioma cells.

Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4672-4680 ◽  
Author(s):  
Shabana Jaffer ◽  
Oksana Shynlova ◽  
Stephen Lye
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Mtor Signaling Pathway ◽  
Insulin Receptor Substrate 1 ◽  
Ovx Rats

Abstract The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.

scholarly journals Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin

2001 ◽  
Vol 21 (15) ◽  
pp. 5050-5062 ◽  
Author(s):  
Atsuko Takano ◽  
Isao Usui ◽  
Tetsuro Haruta ◽  
Junko Kawahara ◽  
Tatsuhito Uno ◽  
...  
Keyword(s):  
Amino Acid ◽  
Insulin Receptor ◽  
Glucose Transport ◽  
Mammalian Target Of Rapamycin ◽  
Proteasomal Degradation ◽  
Target Of Rapamycin ◽  
Insulin Receptor Substrate ◽  
Amino Acid Deprivation ◽  
Insulin Receptor Substrate 1 ◽  
Amino Acid Availability

ABSTRACT A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM) to the cytosol. After prolonged insulin stimulation, inhibition of the redistribution of IRS-1 by rapamycin resulted in increased levels of IRS-1 and the associated phosphatidylinositol (PI) 3-kinase in both the LDM and cytosol, whereas the proteasome inhibitor lactacystin increased the levels only in the cytosol. Since rapamycin but not lactacystin enhances insulin-stimulated 2-deoxyglucose (2-DOG) uptake, IRS-1-associated PI 3-kinase localized at the LDM was suggested to be important in the regulation of glucose transport. The amino acid deprivation attenuated and the amino acid excess enhanced insulin-induced Ser/Thr phosphorylation and subcellular redistribution and degradation of IRS-1 in parallel with the effects on phosphorylation of p70 S6 kinase and 4E-BP1. Accordingly, the amino acid deprivation increased and the amino acid excess decreased insulin-stimulated activation of Akt and 2-DOG uptake. Furthermore, 2-DOG uptake was affected by amino acid availability even when the degradation of IRS-1 was inhibited by lactacystin. We propose that subcellular redistribution of IRS-1, regulated by the mTOR-dependent pathway, facilitates proteasomal degradation of IRS-1, thereby down-regulating Akt, and that the pathway also negatively regulates insulin-stimulated glucose transport, probably through the redistribution of IRS-1. This work identifies a novel function of mTOR that integrates nutritional signals and metabolic signals of insulin.

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