In vivo ethanol decreases phosphorylated MAPK and p70S6 kinase in the developing rat brain

Tsuji, Ryozo; Guizzetti, Marina; Costa, Lucio G.

doi:10.1097/01.wnr.0000071763.92388.41

Cited by 22 publications

(20 citation statements)

References 33 publications

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“…As described above for the heart and brain, liver sections from Akt1-deficient and Akt1 wild-type mice were stained with Hoechst 33258, and the numbers of nuclei were determined for defined fields. The cell density did not differ between Akt1 knockout and wild-type liver sections (1,745 Ϯ 44.6 cells/mm the first two postnatal weeks (69). mTOR is also required for the growth induced by PTEN activation (36).…”

Section: Comparison Of Akt3 Mutants Tomentioning

confidence: 99%

“…mTOR is also required for the growth induced by PTEN activation (36). Therefore, we evaluated the phosphorylation of ribosomal protein S6, a downstream target of mTOR, in brains isolated from postnatal day 1 mice, in which p70 S6 kinase demonstrates peak activity (69). In Akt3 knockout brains, ribosomal protein S6 phosphorylation was decreased almost 50%.…”

Section: Comparison Of Akt3 Mutants Tomentioning

confidence: 99%

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Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Easton¹,

Cho

Roovers³

et al. 2005

Molecular and Cellular Biology

521

499

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Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1 ؊/؊ mice, which display a proportional decrease in the sizes of all organs, Akt3 ؊/؊ mice present a selective 20% decrease in brain size. Moreover, although Akt1-and Akt3-deficient brains are reduced in size to approximately the same degree, the absence of Akt1 leads to a reduction in cell number, whereas the lack of Akt3 results in smaller and fewer cells. Finally, mammalian target of rapamycin signaling is attenuated in the brains of Akt3؊/؊ but not Akt1 ؊/؊ mice, suggesting that differential regulation of this pathway contributes to an isoform-specific regulation of cell growth.While complex organisms grow toward determinate final sizes, there must be precise regulation within each tissue as well as coordination among organs to reach these final sizes (18,24). The regulation of both cell number and size contributes to the establishment of organ size, whereas cell number appears to be predominant in determining differences between species. Several factors, including circulating hormones and metabolites as well as cell-autonomous signaling cascades, control these processes (31). One of the key extracellular effectors determining organismal size is insulin-like growth factor 1 (IGF1). As demonstrated by genetic studies with mice, IGF1 is required for normal embryonic and postnatal growth (4,43,44,59). In addition, IGF1 controls the sizes of individual organs (43, 59). For example, normal brain growth requires IGF1 (6, 43), as IGF1-deficient brains are reduced in size secondary to a decrease in both cell number and cell size (6,15). Similarly, humans with IGF1 deficiency display severe growth retardation and suffer from mental retardation (75).In addition to extracellular factors, the intracellular signaling pathways determining growth are being uncovered. IGF1 acts through the type 1 IGF receptor to modulate an evolutionarily conserved pathway of molecules involved in the regulation of growth and metabolism (38,53). For many hormones, including IGF1 and insulin, binding to a receptor stimulates its protein tyrosine kinase activity, leading to the phosphorylation of scaffold proteins of the insulin receptor substrate (IRS) family. IRS proteins assemble complexes that include a number of potential signaling proteins, of which the lipid kinase phosphatidylinositol 3-kinase (PI3K) appears to be the most critical for the maintenance of cell size and proliferation (10). PI3K catalyzes the generation of phospha...

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Section: Comparison Of Akt3 Mutants Tomentioning

confidence: 99%

Section: Comparison Of Akt3 Mutants Tomentioning

confidence: 99%

Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Easton¹,

Cho

Roovers³

et al. 2005

Molecular and Cellular Biology

521

499

View full text Add to dashboard Cite

show abstract

“…For ethanol treatments, pups were matched by weight between treatment groups and controls. Ethanol was diluted to 20% (w/v) in water and was administered by intragastric intubation at the dose of 2, 4, or 6 g/kg of body weight, as described previously (43). Each dose was divided into two equal doses given 3 h apart.…”

Section: Methodsmentioning

confidence: 99%

Ethanol Induces Cholesterol Efflux and Up-regulates ATP-binding Cassette Cholesterol Transporters in Fetal Astrocytes

Guizzetti

Chen

Oram

et al. 2007

Journal of Biological Chemistry

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Cholesterol plays an important role during brain development, since it is involved in glial cell proliferation, neuronal survival and differentiation, and synaptogenesis. Astrocytes produce large amounts of brain cholesterol and produce and release lipoproteins containing apoE that can extract cholesterol from CNS cells for elimination. We hypothesized that some of the deleterious effects of ethanol in the developing brain may be due to the disruption of cholesterol homeostasis in astrocytes. This study investigates the effect of ethanol on cholesterol efflux mediated by ATP-binding cassette (ABC) cholesterol transporters. In fetal rat astrocytes in culture, ethanol caused a concentration-dependent increase in cholesterol efflux and increased the levels of ABCA1 starting at 25 mM. Similar effects of ethanol on cholesterol efflux and ABCA1 were also observed in fetal human astrocytes. In addition, ABCA1 levels were increased in the brains of 7-day-old pups treated for 3 days with 2, 4, or 6 g/kg ethanol. Ethanol also increased apoE release from fetal rat astrocytes, and conditioned medium prepared from ethanol-treated astrocytes extracted more cholesterol than conditioned medium from untreated cells. In addition, ethanol increased the levels of another cholesterol transporter, ABCG1. Ethanol did not affect cholesterol synthesis and reduced the levels of intracellular cholesterol in rat astrocytes. Retinoic acid, which induces teratogenic effects similarly to ethanol, also caused up-regulation of ABCA1 and ABCG1.

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“…Ethanol has been shown to either inhibit (Seiler et al, 2001;Kalluri and Ticku, 2002) or potentiate ERK activity (Roivainen et al, 1995;Kalluri and Ticku, 2003). Long-term ethanol treatment of rat pups on postnatal days 4 to 7 resulted in decreased phosphorylation of ERK and p70S6 kinase in the cerebral cortex, and ERK was suggested to play a role in alcohol-induced neurotoxicity on the developing molpharm.aspetjournals.org brain (Tsuji et al, 2003). Kalluri and Ticku (2003) recently reported that short-term treatment with ethanol inhibits phosphorylation, whereas long-term ethanol treatment increases phosphorylation of mitogen-activated protein kinase in fetal cortical neurons.…”

Section: Fig 6 Effect Of Long-term Ethanol Treatment On Cam Kinasesmentioning

confidence: 99%

Potential Role of cAMP Response Element-Binding Protein in Ethanol-InducedN-Methyl-d-aspartate Receptor 2B Subunit Gene Transcription in Fetal Mouse Cortical Cells

2005

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We have shown previously that long-term ethanol treatment causes an up-regulation of N-methyl-D-aspartate (NMDA) receptor 2B subunit (NR2B) number and function in cultured fetal mouse cortical neurons. To examine the intracellular signaling pathways involved in this NR2B gene transcription, we have subjected fetal cortical neurons to long-term treatment with ethanol and studied its effect on cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase (ERK) levels by Western blot and enzyme-linked immunosorbent assay. We find a significant increase in phosphorylated CREB, without change in total CREB protein, in cells treated with ethanol for 5 days. Long-term ethanol treatment did not increase levels of both total and phospho-ERK in serum-free medium, whereas it did increase ERK phosphorylation in medium containing serum, without affecting total ERK levels. CREB phosphorylation was increased by ethanol treatment in both media, irrespective of the presence of serum. Electrophoretic mobility shift assay, using a 25-base pair (bp) double-stranded DNA fragment containing the cyclic AMP response element (CRE)-like sequence of the NR2B promoter as 32 P-labeled probe, showed an increase in specific CRE binding to nuclear proteins isolated from cells undergoing long-term ethanol treatment. A 467-bp DNA fragment of the NR2B promoter containing the CRE sequence cloned into the luciferase vector exhibited high reporter activity in transient cotransfection assay of mouse cortical neurons, and ethanol treatment increased this activity. Introducing site-directed mutation in the CRE sequence significantly reduced the reporter activity relative to the wild-type construct, and it also abolished the stimulatory effect by ethanol. Our results indicate that CREB is probably involved in mediating ethanol-induced up-regulation of NR2B gene.

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In vivo ethanol decreases phosphorylated MAPK and p70S6 kinase in the developing rat brain

Cited by 22 publications

References 33 publications

Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Role for Akt3/Protein Kinase Bγ in Attainment of Normal Brain Size

Ethanol Induces Cholesterol Efflux and Up-regulates ATP-binding Cassette Cholesterol Transporters in Fetal Astrocytes

Potential Role of cAMP Response Element-Binding Protein in Ethanol-InducedN-Methyl-d-aspartate Receptor 2B Subunit Gene Transcription in Fetal Mouse Cortical Cells

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