GW8510 increases insulin expression in pancreatic alpha cells through activation of p53 transcriptional activity.

PLoS One
Authors
Keywords
Abstract

BACKGROUND: Expression of insulin in terminally differentiated non-beta cell types in the pancreas could be important to treating type-1 diabetes. Previous findings led us to hypothesize involvement of kinase inhibition in induction of insulin expression in pancreatic alpha cells.

METHODOLOGY/PRINCIPAL FINDINGS: Alpha (αTC1.6) cells and human islets were treated with GW8510 and other small-molecule inhibitors for up to 5 days. Alpha cells were assessed for gene- and protein-expression levels, cell-cycle status, promoter occupancy status by chromatin immunoprecipitation (ChIP), and p53-dependent transcriptional activity. GW8510, a putative CDK2 inhibitor, up-regulated insulin expression in mouse alpha cells and enhanced insulin secretion in dissociated human islets. Gene-expression profiling and gene-set enrichment analysis of GW8510-treated alpha cells suggested up-regulation of the p53 pathway. Accordingly, the compound increased p53 transcriptional activity and expression levels of p53 transcriptional targets. A predicted p53 response element in the promoter region of the mouse Ins2 gene was verified by chromatin immunoprecipitation (ChIP). Further, inhibition of Jun N-terminal kinase (JNK) and p38 kinase activities suppressed insulin induction by GW8510.

CONCLUSIONS/SIGNIFICANCE: The induction of Ins2 by GW8510 occurred through p53 in a JNK- and p38-dependent manner. These results implicate p53 activity in modulation of Ins2 expression levels in pancreatic alpha cells, and point to a potential approach toward using small molecules to generate insulin in an alternative cell type.

Year of Publication
2012
Journal
PLoS One
Volume
7
Issue
1
Pages
e28808
Date Published
2012
ISSN
1932-6203
URL
DOI
10.1371/journal.pone.0028808
PubMed ID
22242153
PubMed Central ID
PMC3252286
Links
Grant list
R37 GM038627 / GM / NIGMS NIH HHS / United States
DP2 DK083048 / DK / NIDDK NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
GM38627 / GM / NIGMS NIH HHS / United States
DP2-DK083048 / DK / NIDDK NIH HHS / United States