TY - JOUR
T1 - Transcriptional activation of the proglucagon gene by lithium and β-catenin in intestinal endocrine L cells
AU - Ni, Zuyao
AU - Anini, Younes
AU - Fang, Xianjun
AU - Mills, Gordon
AU - Brubaker, Patricia L.
AU - Jin, Tianru
PY - 2003/1/10
Y1 - 2003/1/10
N2 - The proglucagon gene encodes several peptide hormones that regulate blood glucose homeostasis, growth of the small intestine, and satiety. Among them, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and inhibits eating and drinking in fasted rats. Although proglucagon transcription and GLP-1 synthesis were shown to be activated by forskolin and other protein kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE) only moderately attenuates the proglucagon gene promoter in response to PKA activation. Therefore, PKA may activate proglucagon transcription via a mechanism independent of the CRE motif. Recently, PKA was shown to phosphorylate and inactivate GSK-3β, a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3β, activates proglucagon gene transcription and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag. The activation was also observed in primary fetal rat intestinal cell (FRIC) cultures, but not in a pancreatic A cell line. Co-transfection of β-catenin, a downstream effector of GSK-3β activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3β at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free β-catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.
AB - The proglucagon gene encodes several peptide hormones that regulate blood glucose homeostasis, growth of the small intestine, and satiety. Among them, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and inhibits eating and drinking in fasted rats. Although proglucagon transcription and GLP-1 synthesis were shown to be activated by forskolin and other protein kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE) only moderately attenuates the proglucagon gene promoter in response to PKA activation. Therefore, PKA may activate proglucagon transcription via a mechanism independent of the CRE motif. Recently, PKA was shown to phosphorylate and inactivate GSK-3β, a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3β, activates proglucagon gene transcription and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag. The activation was also observed in primary fetal rat intestinal cell (FRIC) cultures, but not in a pancreatic A cell line. Co-transfection of β-catenin, a downstream effector of GSK-3β activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3β at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free β-catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.
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U2 - 10.1074/jbc.M206006200
DO - 10.1074/jbc.M206006200
M3 - Article
C2 - 12421827
AN - SCOPUS:0037428472
SN - 0021-9258
VL - 278
SP - 1380
EP - 1387
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 2
ER -