scholarly journals mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition

2009 ◽  
Vol 29 (18) ◽  
pp. 5136-5147 ◽  
Author(s):  
Prashanth T. Bhaskar ◽  
Veronique Nogueira ◽  
Krushna C. Patra ◽  
Sang-Min Jeon ◽  
Youngkyu Park ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Hypoxia Inducible Factor ◽  
Feedback Mechanism ◽  
Serum Deprivation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Hexokinase Ii ◽  
Negative Feedback Mechanism ◽  
Glut1 Expression ◽  
Induced Apoptosis

ABSTRACT The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both an increased level and the sustained translation of HIF1α mRNA. Sustained glycogen synthase kinase 3β inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1α abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2 −/ − cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2 −/ − cells to serum deprivation-induced apoptosis.

scholarly journals ERK1/2 Antagonizes Glycogen Synthase Kinase-3β-induced Apoptosis in Cortical Neurons

2002 ◽  
Vol 277 (51) ◽  
pp. 49577-49584 ◽  
Author(s):  
Michal Hetman ◽  
Shih-Ling Hsuan ◽  
Agata Habas ◽  
Matthew J. Higgins ◽  
Zhengui Xia
Keyword(s):  
Cortical Neuron ◽  
Cortical Neurons ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Activation ◽  
Induced Apoptosis ◽  
Neuron Apoptosis ◽  
Constitutively Active

Inhibition of glycogen synthase kinase-3β (GSK3β) is one of the mechanisms by which phosphatidylinositol 3-kinase (PI3K) activation protects neurons from apoptosis. Here, we report that inhibition of ERK1/2 increased the basal activity of GSK3β in cortical neurons and that both ERK1/2 and PI3K were required for brain-derived neurotrophic factor (BDNF) suppression of GSK3β activity. Moreover, cortical neuron apoptosis induced by expression of recombinant GSK3β was inhibited by coexpression of constitutively active MKK1 or PI3K. Activation of both endogenous ERK1/2 and PI3K signaling pathways was required for BDNF to block apoptosis induced by expression of recombinant GSK3β. Furthermore, cortical neuron apoptosis induced by LY294002-mediated activation of endogenous GSK3β was blocked by expression of constitutively active MKK1 or by BDNF via stimulation of the endogenous ERK1/2 pathway. Although both PI3K and ERK1/2 inhibited GSK3β activity, neither had an effect on GSK3β phosphorylation at Tyr-216. Interestingly, PI3K (but not ERK1/2) induced the inhibitory phosphorylation of GSK3β at Ser-9. Significantly, coexpression of constitutively active MKK1 (but not PI3K) still suppressed neuronal apoptosis induced by expression of the GSK3β(S9A) mutant. These data suggest that activation of the ERK1/2 signaling pathway protects neurons from GSK3β-induced apoptosis and that inhibition of GSK3β may be a common target by which ERK1/2 and PI3K protect neurons from apoptosis. Furthermore, ERK1/2 inhibits GSK3β activity via a novel mechanism that is independent of Ser-9 phosphorylation and likely does not involve Tyr-216 phosphorylation.

scholarly journals Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen–glucose deprivation-induced apoptosis in primary rat cortical neuronal cells

2008 ◽  
Vol 198 (3) ◽  
pp. 511-521 ◽  
Author(s):  
Hyunju Chung ◽  
Sanghee Seo ◽  
Minho Moon ◽  
Seungjoon Park
Keyword(s):  
Glycogen Synthase ◽  
Glucose Deprivation ◽  
Glycogen Synthase Kinase ◽  
Protective Effects ◽  
Glycogen Synthase Kinase 3Β ◽  
Phosphatidylinositol 3 Kinase ◽  
Unacylated Ghrelin ◽  
Gsk 3Β ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Only acylated ghrelin (AG) binds GH secretagog receptor 1a (GHS-R1a) and has central endocrine activities. An anti-apoptotic effect of AG in neuronal cells has recently been reported. However, whether there is a neuroprotective effect of unacylated ghrelin (UAG), the most abundant form of ghrelin in plasma, is still unknown. Therefore, we investigated whether UAG was neuroprotective against ischemic neuronal injury using primary cultured rat cortical neurons exposed to oxygen and glucose deprivation (OGD). Both AG and UAG inhibited OGD-induced apoptosis. Exposure of cells to the receptor-specific antagonist d-Lys-3-GHRH-6 abolished the protective effects of AG against OGD, whereas those of UAG were preserved, suggesting the involvement of a receptor that is distinct from GHS-R1a. Chemical inhibition of MAPK and phosphatidylinositol-3-kinase (PI3K) blocked the anti-apoptotic effects of AG and UAG. Ghrelin siRNA enhanced apoptosis either during OGD or even in normoxic conditions. The protective effects of AG and UAG were accompanied by an increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, Akt, and glycogen synthase kinase-3β (GSK-3β). Furthermore, treatment of cells with AG or UAG resulted in nuclear translocation of β-catenin. In addition, both AG and UAG increased the Bcl-2/Bax ratio, prevented cytochrome c release, and inhibited caspase-3 activation. The data indicate that, independent of acylation, ghrelin can function as a neuroprotective agent that inhibits apoptotic pathways. These effects may be mediated via activation of the MAPK and PI3K/Akt pathways. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β and stabilization of β-catenin contribute to the anti-apoptotic effects of ghrelin.

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