Biological functions of ternary complex factors in pancreatic beta-cells

• Applicant: Professor Dr. Gerald Thiel
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 236732209

The research projects aims to elucidate the biological functions of ternary complex factors (TCF) in pancreatic beta-cells of transgenic mice. The TCFs interact with the serum-response factor, generating a ternary nucleoprotein complex. The TCFs are key regulators of serum-response element-mediated transcription. TCF proteins also influence transcription mediated by the transcription factor AP-1. Elk-1, a member of the TCF family of transcription factors, is activated in glucose-treated pancreatic beta-cells and has been correlated with cellular growth and/or apoptosis. We have generated conditional transgenic mice expressing dominant-negative mutant of Elk-1 in pancreatic beta-cells. The mutant interferes with DNA and SRF-binding of all TCF proteins and thus impairs the biological functions of the entire TCF family. First qRT-PCR-results obtained in the analysis of the newly generated transgenic mice revealed that beta-cell-specific expression of the dominant-negative mutant of Elk-1 reduced expression of Pdx-1 and insulin in pancreatic beta-cells. The investigation aims to elucidate the impact of transgene expression upon glucose homeostasis, insulin release, proliferation and apoptosis. In addition, TCF target genes will be identified using the microarray technology. The identification of new TCF-regulated candidate genes that may influence insulin biosynthesis and secretion, glucose homeostasis, beta-cell proliferation and cell death may open new routes to study the development of diabetes.

• DFG Programme: Research Grants
• International Connection: Belgium
• Participating Persons: Professor Dr. Michael D. Menger; Professor Dr. Frans Schuit