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Chem Biol DOI:10.1016/j.chembiol.2013.10.013

A small-molecule inducer of PDX1 expression identified by high-throughput screening.

Publication TypeJournal Article
Year of Publication2013
AuthorsYuan, Y, Hartland, K, Boskovic, Z, Wang, Y, Walpita, D, Lysy, PA, Zhong, C, Young, DW, Kim, Y-K, Tolliday, NJ, Sokal, EM, Schreiber, SL, Wagner, BK
JournalChem Biol
Volume20
Issue12
Pages1513-22
Date Published2013 Dec 19
ISSN1879-1301
KeywordsAnimals, Carcinoma, Ductal, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays, Homeodomain Proteins, Humans, Mice, Polymerase Chain Reaction, Promoter Regions, Genetic, Small Molecule Libraries, Trans-Activators, Transcriptional Activation
Abstract

Pancreatic and duodenal homeobox 1 (PDX1), a member of the homeodomain-containing transcription factor family, is a key transcription factor important for both pancreas development and mature β cell function. The ectopic overexpression of Pdx1, Neurog3, and MafA in mice reprograms acinar cells to insulin-producing cells. We developed a quantitative PCR-based gene expression assay to screen more than 60,000 compounds for expression of each of these genes in the human PANC-1 ductal carcinoma cell line. We identified BRD7552, which upregulated PDX1 expression in both primary human islets and ductal cells, and induced epigenetic changes in the PDX1 promoter consistent with transcriptional activation. Prolonged compound treatment induced both insulin mRNA and protein and also enhanced insulin expression induced by the three-gene combination. These results provide a proof of principle for identifying small molecules that induce expression of transcription factors to control cellular reprogramming.

DOI10.1016/j.chembiol.2013.10.013
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24290880?dopt=Abstract

Alternate JournalChem. Biol.
PubMed ID24290880
PubMed Central IDPMC3927138
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
/ / Howard Hughes Medical Institute / United States
GM38627 / GM / NIGMS NIH HHS / United States