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Ethanol impairs insulin-stimulated neuronal survival in the developing brain role of pten phosphatase

Authors
Xu J.Yeon J.E.Chang H.Tison G.Chen G.J.Wands J.De la Monte S.
Issue Date
2003
Keywords
PTEN; neuron; survival; brain
Citation
Journal of Biological Chemistry, v.278, no.29, pp 26929 - 26937
Pages
9
Indexed
SCOPUS
Journal Title
Journal of Biological Chemistry
Volume
278
Number
29
Start Page
26929
End Page
26937
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/21564
DOI
10.1074/jbc.M300401200
ISSN
0021-9258
1083-351X
Abstract
Gestational exposure to ethanol causes fetal alcohol syndrome, which is associated with cerebellar hypoplasia. Previous in vitro studies demonstrated ethanol-impaired neuronal survival with reduced signaling through the insulin receptor (IRβ). We examined insulin signaling in an experimental rat model of chronic gestational exposure to ethanol in which the pups exhibited striking cerebellar hypoplasia with increased apoptosis. Immunoprecipitation and Western blot analyses detected reduced levels of tyrosyl-phosphorylated IRβ, tyrosyl-phosphorylated insulin receptor substrate-1 (IRS-1), and p85-associated IRS-1 but no alterations in IRβ, IRS-1, or p85 protein expression in cerebellar tissue from ethanol-exposed pups. In addition, ethanol exposure significantly reduced the levels of total phosphoinositol 3-kinase, Akt kinase, phospho-BAD (inactive), and glyceraldehyde-3-phosphate dehydrogenase and increased the levels of glycogen synthase kinase-3 activity, activated BAD, phosphatase and tensin homolog deleted in chromosome 10 (PTEN) protein, and PTEN phosphatase activity in cerebellar tissue. Cerebellar neurons isolated from ethanol-exposed pups had reduced levels of insulin-stimulated phosphoinositol 3-kinase and Akt kinase activities and reduced insulin inhibition of PTEN and glycogen synthase kinase-3 activity. The results demonstrate that cerebellar hypoplasia produced by chronic gestational exposure to ethanol is associated with impaired survival signaling through insulin-regulated pathways, including failure to suppress PTEN function.
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Guro Hospital (Department of Gastroenterology and Hepatology, Guro Hospital)
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