Mammalian target of rapamycin complex 1 activation in podocytes promotes cellular crescent formation

2014 ◽  
Vol 307 (9) ◽  
pp. F1023-F1032 ◽  
Author(s):  
Junhua Mao ◽  
Zhifeng Zeng ◽  
Zhuo Xu ◽  
Jiangzhong Li ◽  
Lei Jiang ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Target Of Rapamycin ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Mtorc1 Signaling ◽  
Cellular Crescent ◽  
Underlying Mechanisms ◽  
Mtorc1 Activation ◽  
Glomerular Tuft

Podocytes play a key role in the formation of cellular crescents in experimental and human diseases. However, the underlying mechanisms for podocytes in promoting crescent formation need further investigation. Here, we demonstrated that mammalian target of rapamycin complex 1 (mTORC1) signaling was remarkably activated and hypoxia-inducible factor (HIF) 1α expression was largely induced in cellular crescents from patients with crescentic glomerular diseases. Specific deletion of Tsc1 in podocytes led to mTORC1 activation in podocytes and kidney dysfunction in mice. Interestingly, 33 of 36 knockouts developed cellular or mixed cellular and fibrous crescents at 7 wk of age (14.19 ± 3.86% of total glomeruli in knockouts vs. 0% in control littermates, n = 12–36, P = 0.04). All of the seven knockouts developed crescents at 12 wk of age (30.92 ± 11.961% of total glomeruli in knockouts vs. 0% in control littermates, n = 4–7, P = 0.002). Most notably, bridging cells between the glomerular tuft and the parietal basement membrane as well as the cellular crescents were immunostaining positive for WT1, p-S6, HIF1α, and Cxcr4. Furthermore, continuously administrating rapamycin starting at 7 wk of age for 5 wk abolished crescents as well as the induction of p-S6, HIF1α, and Cxcr4 in the glomeruli from the knockouts. Together, it is concluded that mTORC1 activation in podocytes promotes cellular crescent formation, and targeting this signaling may shed new light on the treatment of patients with crescentic glomerular diseases.

scholarly journals Glucagon acts in a dominant manner to repress insulin-induced mammalian target of rapamycin complex 1 signaling in perfused rat liver

2009 ◽  
Vol 297 (2) ◽  
pp. E410-E415 ◽  
Author(s):  
Jamie I. Baum ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Protein Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Perfused Rat Liver ◽  
S6 Kinase ◽  
Akt Phosphorylation ◽  
Ribosomal Protein S6 ◽  
Mtorc1 Signaling ◽  
Kinase A

The opposing actions of insulin and glucagon on hepatic carbohydrate metabolism are well documented. In contrast, relatively little is known about how the two hormones interact to regulate hepatic protein metabolism. Previously, we reported that glucagon in the absence of insulin represses signaling through the mammalian target of rapamycin complex 1 (mTORC1). In the present study, we sought to determine whether or not the action of one hormone would dominate over the other in the regulation of mTORC1 signaling. Livers were perfused in situ with medium containing either no added hormones (control), 10 nM insulin, 100 nM glucagon, or a combination of the hormones. Compared with control livers, insulin stimulated Akt phosphorylation and mTORC1 signaling, as assessed by increased phosphorylation of the mTORC1 targets eIF4E-binding protein (4E-BP)1 and ribosomal protein S6 kinase (S6K)1, and promoted assembly of the eIF4G·eIF4E complex. Glucagon alone had no effect on mTORC1 signaling but stimulated the activity of protein kinase A (PKA). In the presence of a combination of insulin and glucagon, Akt and TSC2 phosphorylation and PKA activity were all increased compared with controls. However, mTORC1 signaling was repressed compared with livers perfused with medium containing insulin alone, and this effect was associated with reduced assembly of the mTORC1·eIF3 complex. Overall, the results suggest that glucagon acts in a dominant manner to repress insulin-induced mTORC1 signaling, which is in contrast to previous studies showing a dominant action of insulin in the control of hepatic gluconeogenesis.

scholarly journals NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth

2009 ◽  
Vol 29 (15) ◽  
pp. 4250-4261 ◽  
Author(s):  
Marianne F. James ◽  
Sangyeul Han ◽  
Carolyn Polizzano ◽  
Scott R. Plotkin ◽  
Brendan D. Manning ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Suppressor Activity ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Tumor Suppressive Function ◽  
Mtorc1 Activation

ABSTRACT Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.

scholarly journals Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing

2017 ◽  
Vol 216 (7) ◽  
pp. 1949-1957 ◽  
Author(s):  
Bernadette Carroll ◽  
Glyn Nelson ◽  
Yoana Rabanal-Ruiz ◽  
Olena Kucheryavenko ◽  
Natasha A. Dunhill-Turner ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Primary Cilia ◽  
Human Fibroblasts ◽  
Mammalian Target Of Rapamycin ◽  
Senescent Cell ◽  
Cell Senescence ◽  
Growth Factor Signaling ◽  
Mtorc1 Signaling ◽  
Underlying Mechanisms

Mammalian target of rapamycin complex 1 (mTORC1) and cell senescence are intimately linked to each other and to organismal aging. Inhibition of mTORC1 is the best-known intervention to extend lifespan, and recent evidence suggests that clearance of senescent cells can also improve health and lifespan. Enhanced mTORC1 activity drives characteristic phenotypes of senescence, although the underlying mechanisms responsible for increased activity are not well understood. We have identified that in human fibroblasts rendered senescent by stress, replicative exhaustion, or oncogene activation, mTORC1 is constitutively active and resistant to serum and amino acid starvation. This is driven in part by depolarization of senescent cell plasma membrane, which leads to primary cilia defects and a resultant failure to inhibit growth factor signaling. Further, increased autophagy and high levels of intracellular amino acids may act to support mTORC1 activity in starvation conditions. Interventions to correct these phenotypes restore sensitivity to the mTORC1 signaling pathway and cause death, indicating that persistent signaling supports senescent cell survival.

scholarly journals p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage

2013 ◽  
Vol 289 (7) ◽  
pp. 4083-4094 ◽  
Author(s):  
Maren Cam ◽  
Hemant K. Bid ◽  
Linlin Xiao ◽  
Gerard P. Zambetti ◽  
Peter J. Houghton ◽  
...  
Keyword(s):  
Dna Damage ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Parallel Pathways ◽  
Mtorc1 Signaling
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