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PLoS One. 2012;7(1):e28808. doi: 10.1371/journal.pone.0028808. Epub 2012 Jan 5.

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

Author information

1
Chemical Biology Program, the Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.

Erratum in

  • PLoS One. 2012;7(3). doi: 10.1371/annotation/c41ac082-32ac-4837-b4ed-9fd8ad91c1e0. He, Kaihui Hu [corrected to He, Kai Hui Hu].

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.

PMID:
22242153
PMCID:
PMC3252286
DOI:
10.1371/journal.pone.0028808
[Indexed for MEDLINE]
Free PMC Article
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