Faculty Collaboration Database

PGJ2-stimulated beta-cell apoptosis is associated with prolonged UPR activation. Am J Physiol Endocrinol Metab 2007 Apr;292(4):E1052-61

Date

12/07/2006

Pubmed ID

17148750

DOI

10.1152/ajpendo.00274.2006

Scopus ID

2-s2.0-34047231566 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligands have been shown to possess anti-inflammatory properties that include the inhibition of transcription factor activation and the expression of inflammatory genes. Using pancreatic beta-cells, we have shown that PPARgamma ligands such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) attenuate interferon-gamma-induced signal transducer and activator of transcription 1 activation and interleukin (IL)-1beta-induced nuclear factor-kappaB activation by a pathway that correlates with endoplasmic reticulum stress and the induction of the unfolded protein response (UPR). The UPR is a conserved cellular response activated by a number of cell stressors and is believed to alleviate the stress and promote cell survival. However, prolonged activation of the UPR results in cellular death by apoptosis. In this report, we have examined the effects of PGJ(2) on UPR activation and the consequences of this activation on cell survival. Consistent with induction of a cell death pathway, treatment of rat islets and RINm5F cells for 24 h with PGJ(2) results in caspase-3 activation and caspase-dependent beta-cell death. The actions of these ligands do not appear to be selective for beta-cells, because PGJ(2) stimulates macrophage apoptosis in a similar fashion. Associated with cell death is the enhanced phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha), and in cells expressing a mutant of eIF2alpha that cannot be phosphorylated, the stimulatory actions of PGJ(2) on caspase-3 activation are augmented. These findings suggest that, whereas PGJ(2)-induced UPR activation is associated with an inhibition of cytokine signaling, prolonged UPR activation results in cell death, and that eIF2alpha phosphorylation may function in a protective manner to attenuate cell death.

Author List

Chambers KT, Weber SM, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Caspase 3
Cells, Cultured
Enzyme Activation
Eukaryotic Initiation Factor-2
Insulin-Secreting Cells
Insulinoma
Ligands
Macrophages
Male
Mice
Mutation
PPAR gamma
Pancreatic Neoplasms
Phosphorylation
Prostaglandin D2
Protein Folding
Rats
Rats, Sprague-Dawley
Time Factors