Howard Hughes Medical Institute Investigator
The modification of cellular proteins with ubiquitin is a key regulatory process in all eukaryotes. Ubiquitination can affect the localization, binding partners, or stability of modified proteins, and thereby controls diverse processes such as the cell cycle, differentiation, transcription, or endocytosis. Specific enzymes, referred to as ubiquitin ligases, catalyze the ubiquitination of substrates, whereas deubiquitinating enzymes are able to remove ubiquitin and terminate ubiquitin-dependent signaling. Several ubiquitin ligases and deubiquitinating enzymes are essential for controlling proliferation and differentiation in mammals.
Consequently, their misregulation causes tumorigenesis or allows cancer cells to evade chemotherapy. We are interested in identifying ubiquitin ligases and deubiquitinating enzymes that regulate proliferation and differentiation in somatic cells and in stem cells. Both work by us and by others have delineated differences in cell cycle control between somatic cells and stem cells, and thus, isolating enzymes required in either stem cells or somatic cells allows us to devise strategies of impeding the proliferation of cancer stem cells. Additionally, we have developed novel strategies to isolate substrates of ubiquitin ligases in stem cells using concentrated extracts of embryonic stem cells. Identifying substrates of critical ubiquitination enzymes provides us with insight into how proliferation is controlled by ubiquitination in stem cells.
Following the discovery of both ubiquitin ligases and substrates, we will proceed to dissecting the biochemical mechanism of ubiquitination. Thereby, we will develop quantitative assays allowing us to screen for small-molecule inhibitors of ubiquitin ligases in stem cells, which can be tested for the capacity to interfere with stem cell proliferation or differentiation.