Transcription factor 11 (TCF 11) is a transcriptional regulator of proteasome subunit genes - what in turn regulates TCF 11 activation?

• Applicants: Dr. Annett Koch; Professorin Dr. Elke Beate Krüger
• Subject Area: Cell Biology
• Term: from 2010 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 190868493

Protein homeostasis is based on a combination of synthesis, quality control and destruction. Disturb-ance of this sensitive balance may result in disorders like neurodegenerative diseases or cancer. A primary station for quality control and destruction is the ubiquitin-proteasome-system. We have shown that the treatment with proteasome inhibitors leads to a transient and concerted upregulation of all 26S proteasome subunit mRNAs in mammalian cells. The higher levels of subunits result in an increased de novo formation of functional proteasomes. Very recently we identified TCF11, a transcription factor interacting with antioxidant response elements in the promoter region of proteasomal subunits. By this means TCF11 induces their transcription to compensate for reduced proteolytic activity. Under non-inducing conditions TCF11 resides in the endoplasmic reticulum membrane, where its low abundance is ensured by the ER-associated protein degradation system. Proteasome inhibitors promote the nuclear translocation and activation of TCF11. The main focus of this project is to further investigate the TCF11-dependent feedback loop. This includes the analysis of TCF11 activation, which occurs probably by regulated intramembrane proteolysis, as well as its intracellular trafficking, especially its translocation into and out of the nucleus.

• DFG Programme: Research Grants