Transcription factors regulate Forkhead box O1 gene promoter activity in pancreatic ?-cells

Abstract

Background: Transcription factors of the Forkhead box O (Fox O) family have important roles in cellular proliferation, apoptosis, differentiation, and stress resistance. In pancreatic ?-cells, FoxO1 protein plays an important role in ?-cells development. The molecular mechanism of transcriptional regulation of basal FoxO1 gene expression in pancreatic ?-cells is not fully understood. Objectives: Explore the potential transcription factors regulating FoxO1 promoter activity using pancreatic ?-cell line (RINm5F cells) Methods: Promoter screening method, luciferase reporter gene analysis, transient expression assay system, and deletion analysis of a -974/-18 bp 5’ upstream region of the mouse FoxO1 gene were used in this study. Results: An inhibition domain (-974/-321) and an activation domain (-321/-18) was identified through deletion analysis of a -974/-18 bp 5’ upstream region of the mouse FoxO1 gene. Using the promoter screening method, several transcription factors were selected. Luciferase reporter studies showed that these factors could regulate FoxO1 promoter activity in RINm5F cells. Among these factors, cAMP response-element binding protein (CREB) could positively regulate FoxO1 promoter activity. Signal transducer and activator of transcription 1 (STAT1) played a negative role on FoxO1 promoter. In addition, ETS oncogene family member Elk-1 did not affect the FoxO1 promoter activity. Conclusion: Two transcription factors (CREB and STAT1) could effectively regulate the mouse FoxO1 gene promoter activity. Keywords: CREB, FoxO1, promoter activity, STAT1