Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases

The pancreatic beta cell is sensitive to even small changes in PDX1 protein levels; consequently, <i>Pdx1</i> haploinsufficiency can inhibit beta cell growth and decrease insulin biosynthesis and gene expression, leading to compromised glucose-stimulated insulin secretion. Using metaboli...

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Autores principales: Humphrey, Rohan K., Yu, Shu-Mei, Flores, Luis Emilio, Jhala, Ulupi S.
Formato: Articulo
Lenguaje:Inglés
Publicado: 2010
Materias:
Ciencias Médicas
Glucose
PDX1
AKT
GSK3
Endocrinología
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/104636
http://hdl.handle.net/11336/96675
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-104636
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Médicas
Glucose
PDX1
AKT
GSK3
Endocrinología
spellingShingle Ciencias Médicas
Glucose
PDX1
AKT
GSK3
Endocrinología
Humphrey, Rohan K.
Yu, Shu-Mei
Flores, Luis Emilio
Jhala, Ulupi S.
Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
topic_facet Ciencias Médicas
Glucose
PDX1
AKT
GSK3
Endocrinología
description The pancreatic beta cell is sensitive to even small changes in PDX1 protein levels; consequently, <i>Pdx1</i> haploinsufficiency can inhibit beta cell growth and decrease insulin biosynthesis and gene expression, leading to compromised glucose-stimulated insulin secretion. Using metabolic labeling of primary islets and a cultured β cell line, we show that glucose levels modulate PDX1 protein phosphorylation at a novel C-terminal GSK3 consensus that maps to serines 268 and 272. A decrease in glucose levels triggers increased turnover of the PDX1 protein in a GSK3-dependent manner, such that PDX1 phosphomutants are refractory to the destabilizing effect of low glucose. Glucose-stimulated activation of AKT and inhibition of GSK3 decrease PDX1 phosphorylation and delay degradation. Furthermore, direct pharmacologic inhibition of AKT destabilizes, and inhibition of GSK3 increases PDX1 protein stability. These studies define a novel functional role for the PDX1 C terminus in mediating the effects of glucose and demonstrate that glucose modulates PDX1 stability via the AKT-GSK3 axis.
format Articulo
Articulo
author Humphrey, Rohan K.
Yu, Shu-Mei
Flores, Luis Emilio
Jhala, Ulupi S.
author_facet Humphrey, Rohan K.
Yu, Shu-Mei
Flores, Luis Emilio
Jhala, Ulupi S.
author_sort Humphrey, Rohan K.
title Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
title_short Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
title_full Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
title_fullStr Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
title_full_unstemmed Glucose regulates steady-state levels of PDX1 via the reciprocal actions of GSK3 and AKT kinases
title_sort glucose regulates steady-state levels of pdx1 via the reciprocal actions of gsk3 and akt kinases
publishDate 2010
url http://sedici.unlp.edu.ar/handle/10915/104636
http://hdl.handle.net/11336/96675
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AT yushumei glucoseregulatessteadystatelevelsofpdx1viathereciprocalactionsofgsk3andaktkinases
AT floresluisemilio glucoseregulatessteadystatelevelsofpdx1viathereciprocalactionsofgsk3andaktkinases
AT jhalaulupis glucoseregulatessteadystatelevelsofpdx1viathereciprocalactionsofgsk3andaktkinases
bdutipo_str Repositorios
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