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Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci.
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Immanuel kant
May 24, 2012, 8:30:49 PM5/24/12
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Biol Chem. 2010 Dec 31;285(53):41337-47. Epub 2010 Nov 3.
Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase
kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci.
Popkie AP, Zeidner LC, Albrecht AM, D'Ippolito A, Eckardt S, Newsom
DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ.
SourceGraduate Program in Molecular, Cellular and Developmental
Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Abstract
Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3α and Gsk-3β, are
constitutively active, largely inhibitory kinases involved in signal
transduction. Underscoring their biological significance, altered
Gsk-3 activity has been implicated in diabetes, Alzheimer disease,
schizophrenia, and bipolar disorder. Here, we demonstrate that
deletion of both Gsk-3α and Gsk-3β in mouse embryonic stem cells
results in reduced expression of the de novo DNA methyltransferase
Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and
Igf2r and hypomethylation of their corresponding imprinted control
regions. Treatment of wild-type embryonic stem cells and neural stem
cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA
hypomethylation at these imprinted loci. We show that inhibition of
Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of
Akt also results in reduced DNA methylation at these imprinted loci.
Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of
Dnmt3a2 expression. In summary, we have identified a signal
transduction pathway that is capable of altering the DNA methylation
of imprinted loci.
PMID: 21047779
Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase
kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci.
Popkie AP, Zeidner LC, Albrecht AM, D'Ippolito A, Eckardt S, Newsom
DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ.
SourceGraduate Program in Molecular, Cellular and Developmental
Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Abstract
Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3α and Gsk-3β, are
constitutively active, largely inhibitory kinases involved in signal
transduction. Underscoring their biological significance, altered
Gsk-3 activity has been implicated in diabetes, Alzheimer disease,
schizophrenia, and bipolar disorder. Here, we demonstrate that
deletion of both Gsk-3α and Gsk-3β in mouse embryonic stem cells
results in reduced expression of the de novo DNA methyltransferase
Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and
Igf2r and hypomethylation of their corresponding imprinted control
regions. Treatment of wild-type embryonic stem cells and neural stem
cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA
hypomethylation at these imprinted loci. We show that inhibition of
Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of
Akt also results in reduced DNA methylation at these imprinted loci.
Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of
Dnmt3a2 expression. In summary, we have identified a signal
transduction pathway that is capable of altering the DNA methylation
of imprinted loci.
PMID: 21047779
Immanuel kant
May 24, 2012, 8:37:51 PM5/24/12
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