Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids

Shen, Wei; Boyle, David W.; Wisniowski, Paul; Bade, Aashia; Liechty, Edward A.

doi:10.1677/joe.1.06080

Cited by 56 publications

(60 citation statements)

References 44 publications

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“…The latter competes with eIF4G for binding to eIF4E: when 4E-BP1 is hypophosphorylated, it tightly binds eIF4E to form the translationally inactive eIF4E/4E-BP1 complex. By contrast, when 4E-BP1 is phosphorylated, eIF4E is released and presumably available for binding to eIF4G (35). eIF4E, together with eIF4G and EIF4A, forms the eIF4F complex, that is crucially involved in mRNA translation (34).…”

Section: Discussionmentioning

confidence: 99%

“…eIF4E, together with eIF4G and EIF4A, forms the eIF4F complex, that is crucially involved in mRNA translation (34). Phosphorylation of 4E-BP1 induced by growth factors such as insulin and IGF-I has been shown to depend on the Akt/PI3K/mTOR pathway (35), whereas an Akt-unrelated, mTOR-dependent activation has been proposed to results from increased intracellular amino acid availability (35). In a parallel pathway, the eIF2 complex formed by eIF2·, ß and Á, binds the Met-tRNA to the 40S ribosomal subunit to form the 43S initiation complex.…”

Section: Discussionmentioning

confidence: 99%

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β-hydroxy-β-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia

Muscaritoli¹

2011

Int J Oncol

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Abstract. ß-hydroxy-ß-methylbutyrate (HMB), a leucine metabolite, improves muscle mass and function. This study aimed at evaluating the effects of HMB administration in an experimental in vivo model of cancer cachexia (CC). Wistar rats were randomized to receive standard or 4% HMBenriched chow. Rats from both groups were randomized to receive an i.p. inoculum of AH-130 cells (TB). All rats were weighed and sacrificed at day 24. Liver, heart and muscles were dissected and weighed. The protein levels of p-p70S6k, p-eIf2·, p-mTOR and p-4-EB-P1 were evaluated by Western blotting on gastrocnemius muscle (GSN). As expected, the growth of the AH-130 ascites hepatoma induced significant carcass weight and GSN muscle loss. HMB treatment significantly increased GSN and heart weight in controls (p=0.002 and p<0.001, respectively). In HMB-treated TB, body weight was not lost but significantly (p=0.003) increased, and GSN loss was significantly (p=0.04) attenuated with respect to TB. Phosphorylated eIF2· markedly decreased in TB-rats vs. C. Feeding the HMB-enriched diet resulted in decreased p-eIF2· levels in control animals, while no changes could be observed in the TB group. Phosphorylated p70S6K and phosphorylated mTOR were markedly increased by HMB treatment in controls and further increased in TB. Phosphorylated 4-EB-P1 was markedly increased in TB but substantially unaffected by HMB treatment. Administration of HMB attenuates body weight and muscle loss in experimental CC. Increased phosphorylation of key anabolic molecules suggests that these actions are mediated by improved protein anabolism in muscle.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

β-hydroxy-β-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia

Muscaritoli¹

2011

Int J Oncol

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“…It has been reported that PI 3-K/Akt/mTOR and PKC signaling pathways might play a role in increased translational efficiency through these RNA complexes (Angenstein et al, 2002;Wu et al, 2005). Clearly, Akt plays a major role in the regulation of translation through eukaryotic initiation factor 4E (eIF4E)/ binding protein (4EBP1) (Shen et al, 2005). Thus, it is plausible that PI 3-K and PKC signaling are involved in AA-mediated CYP2E1 mRNA translation.…”

Section: Discussionmentioning

confidence: 99%

Acetoacetate Induces CYP2E1 Protein and Suppresses CYP2E1 mRNA in Primary Cultured Rat Hepatocytes

Abdelmegeed

Carruthers

Woodcroft

et al. 2005

J Pharmacol Exp Ther

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The ketone body acetoacetate (AA) in the absence of insulin or in the presence of diabetic insulin levels decreases CYP2E1 mRNA expression in a concentration-and time-dependent manner in primary cultured rat hepatocytes. AA activates p70 ribosomal S6 kinase (p70S6K) and protein kinase C (PKC) by ϳ2-to 2.5-fold, respectively, following 6-h treatment. The AAmediated activation of p70S6K, but not PKC, was abolished by inhibition of PI 3-K with LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] or wortmannin, in agreement with p70S6K being downstream of phosphatidylinositol 3-kinase (PI 3-K). Inhibition of PI 3-K, mTOR with rapamycin, or PKC with bisindolylmaleimide ameliorated the AA-mediated down-regulation of CYP2E1 mRNA expression. Neither the mitogen-activated protein kinase kinase inhibitor PD98059 (2Ј-amino-3Ј-methoxyflavone) nor the p38 mitogen-activated protein kinase inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] ameliorated the AA-mediated suppression of CYP2E1 mRNA expression. Heterogeneous nuclear RNA analysis revealed that AA suppressed CYP2E1 gene transcription by ϳ50% and that inhibition of PI 3-K and PKC diminished this AA-mediated effect on transcription. CYP2E1 mRNA half-life slightly increased from ϳ24 h in untreated hepatocytes to ϳ32 h in AA-treated cells. Interestingly, AA increased CYP2E1 protein levels by ϳ2-and 2.5-fold at 24 and 48 h, respectively. DL-␤-Hydroxybutyrate was without effect. Polysomal distribution studies revealed that AA increased the proportion of RNA associated with the actively translated polysomal fractions versus the 40S to 60S untranslated fractions by ϳ40%. CYP2E1 protein half-life increased from ϳ8 h in untreated hepatocytes to ϳ24 in AA-treated cells. These data show that AA decreases CYP2E1 mRNA expression through inhibition of gene transcription while simultaneously elevating CYP2E1 protein levels through increased translation and decreased protein degradation.Acetoacetate (AA) and DL-␤-hydroxybutyrate (3HB) comprise two major ketone bodies, which are produced primarily in the liver. Ketone bodies are considered an emergency source of glucose (Casazza et al., 1984). In humans, ketone bodies (AA plus 3HB) with plasma concentrations higher than 1 mM are considered hyperketonemic. Ketone body concentrations may be elevated up to 10 mM in severe ketosis, relative to concentrations less than 0.5 mM under normal physiologic conditions (Jain et al., 2003). Hyperketonemia is a very common feature in diabetes mellitus.AA and 3HB effects on CYP2E1 expression remain controversial. An increase in CYP2E1 protein and/or activity has been associated with hyperketonemia (Shimojo, 1994); however, neither AA nor 3HB elevated CYP2E1 mRNA levels in the presence of insulin in primary cultured rat hepatocytes (Zangar and Novak, 1997) or in vivo (Barnett et al., 1992). In addition, we have reported that AA, but not 3HB, in the absence of insulin substantially decreased CYP2E1 mRNA levels in primary cultured rat hepatocytes c...

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“…Phosphorylation of Eif4ebp1 leading to its dissociation from Eif4E has been implicated at least in part in insulin-mediated enhancement of translation and cell growth (57). Similarly, cyclin-dependent kinase inhibitor 1A (Cdkn1a or p21) is a protein that binds to cyclin complexes and inhibits cell cycle progression (58), and its activation is associated with ER stress and apoptosis of ␤-cells (59).…”

Section: Foxo1 Inhibition Protects Islet ␤-Cellsmentioning

confidence: 99%

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

et al. 2008

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OBJECTIVE—β-Cells are particularly susceptible to fatty acid–induced apoptosis associated with decreased insulin receptor/phosphatidylinositol-3 kinase/Akt signaling and the activation of stress kinases. We examined the mechanism of fatty acid–induced apoptosis of mouse β-cells especially as related to the role played by endoplasmic reticulum (ER) stress–induced Foxo1 activation and whether decreasing Foxo1 activity could enhance cell survival. RESEARCH DESIGN AND METHODS—Mouse insulinoma (MIN6) cells were administered with fatty acids, and the role of Foxo1 in mediating effects on signaling pathways and apoptosis was examined by measuring Foxo1 activity and using dominant-negative Foxo1. RESULTS—Increasing fatty acid concentrations (100–400 μmol/l palmitate or oleate) led to early Jun NH2-terminal kinase (JNK) activation that preceded induction of ER stress markers and apoptosis. Foxo1 activity was increased with fatty acid administration and by pharmacological inducers of ER stress, and this increase was prevented by JNK inhibition. Fatty acids induced nuclear localization of Foxo1 at 4 h when Akt activity was increased, indicating that FoxO1 activation was not mediated by JNK inhibition of Akt. In contrast, fatty acid administration for 24 h was associated with decreased insulin signaling. A dominant-negative Foxo1 adenovirus (Adv-DNFoxo) conferred cells with protection from ER stress and fatty acid–mediated apoptosis. Microarray analysis revealed that fatty acid induction of gene expression was in most cases reversed by Adv-DNFoxo, including the proapoptotic transcription factor CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein). CONCLUSIONS—Early induction of JNK and Foxo1 activation plays an important role in fatty acid–induced apoptosis. Expressing a dominant-negative allele of Foxo1 reduces expression of apoptotic and ER stress markers and promotes β-cell survival from fatty acid and ER stress, identifying a potential therapeutic target for preserving β-cells in type 2 diabetes.

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Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids

Cited by 56 publications

References 44 publications

β-hydroxy-β-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia

β-hydroxy-β-methylbutyrate (HMB) attenuates muscle and body weight loss in experimental cancer cachexia

Acetoacetate Induces CYP2E1 Protein and Suppresses CYP2E1 mRNA in Primary Cultured Rat Hepatocytes

Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis

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