Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based Screen

ABSTRACT: (original Title) Phenothiazine Neuroleptics Signal To The Human Insulin Promoter As Revealed By A Novel Human b-Cell Line Based High-Throughput Screen. To address the current deficiency in human beta-cell models, we have developed a cell line from human islets in which the expression of insulin and other beta-cell restricted genes are modulated by an inducible form of the bHLH transcription factor E47. In an effort to probe the global pattern of gene expression in T6PNE in an unbiased fashion, oligonucleotide microarray analysis was performed on T6PNE in the presence and absence of E47 induction and compared against human islets. Our analysis reveals that T6PNE express a substantial percentage of the b-cell specific geneset, and that this is further enhanced by the induction of E47. This cell line, T6PNE, was then screened against a library of known drugs for those that increase insulin promoter activity. Interestingly, members of the phenothiazine class of neuroleptics increased insulin gene expression upon short term exposure. Chronic treatment, however, resulted in suppression of insulin promoter activity, consistent with the effect of phenothiazines observed clinically to induce diabetes in chronically treated patients. In addition to providing insights into previously unrecognized targets and mechanisms of action of phenothiazines, the novel cell line described here provides a broadly applicable platform for mining new molecular drug targets and central regulators of beta-cell differentiated function. Gene expression studies in: Three human islet samples; Five T6PNE samples; Seven T6PNE induced with E47.

ORGANISM(S): Homo sapiens

SUBMITTER: Roy Williams 

PROVIDER: E-GEOD-18821 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress