GRK 2243 "Understanding Ubiquitylation: From Molecular Mechanisms to Disease"

    Project C4 (completed)

    Control of SREBP stability and transcriptional activity by the ubiquitin system

    Almut Schulze, Nikita Popov

    Metabolic reprogramming is a hallmark of cancer, and oncogenic signalling pathways alter the expression and/or activity of metabolic enzymes to promote macromolecule synthesis and rapid proliferation in cancer cells. We have previously shown that the PI3-kinase/Akt pathway induces lipid biosynthesis via activation of the sterol regulatory element binding proteins (SREBPs), a family of transcription factors controlling the expression of metabolic enzymes. SREBPs are substrates of the FBXW7 ubiquitin ligase, which induces ubiquitylation of these proteins in response to regulatory phosphorylation. While the importance of FBXW7-mediated ubiquitylation in controlling the stability of SREBPs is established, it is not known whether these proteins are also substrates of deubiquitinating enzymes (DUBs). Furthermore, the effect of differential ubiquitylation on transcriptional activity of SREBPs has not been investigated. In this project, we will perform siRNA screens to identify DUBs involved in controlling SREBP ubiquitylation. We will also determine the effects of ubiquitylation on chromatin binding of SREBPs as well as their association with cofactors and components of the basic transcription machinery. Together, the results of this project will further the understanding of the interactions between the ubiquitin system and modulators of gene expression that are relevant for human disease.