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PLoS One DOI:10.1371/journal.pone.0028808

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

Publication TypeJournal Article
Year of Publication2012
AuthorsFomina-Yadlin, D, Kubicek, S, Vetere, A, He, KHui Hu, He, KHu, Schreiber, SL, Wagner, BK
JournalPLoS One
Volume7
Issue1
Pagese28808
Date Published2012
ISSN1932-6203
KeywordsAnimals, Cell Cycle, Cell Line, Glucagon-Secreting Cells, Humans, Indoles, Insulin, Mice, Middle Aged, Models, Biological, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-mdm2, Response Elements, Signal Transduction, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53
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.

URLhttp://dx.plos.org/10.1371/journal.pone.0028808
DOI10.1371/journal.pone.0028808
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22242153?dopt=Abstract

Alternate JournalPLoS ONE
PubMed ID22242153
PubMed Central IDPMC3252286
Grant ListR37 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