Regulation of hypoxia-inducible factors by small ubiquitin-like modifiers

Abstract

The topic of this thesis is the molecular regulation of Hypoxia-Inducible Factors (HIFs) by sumoylation. Hypoxia-Inducible Factors are transcriptional regulators that mediate cell survival during reduced oxygen conditions (hypoxia). HIFs are extensively controlled by post-translational modifications. The aim of this thesis was to obtain novel insight in the posttranslational modification of HIFs by sumoylation. Chapters 1 and 2 are introductions on sumoylation and Hypoxia-Inducible Factors, respectively. A summary of current knowledge is provided based on published literature on both systems. Chapter 3 describes the regulation of HIF-1_ transcriptional activity by sumoylation via a novel SUMO acceptor site. Chapter 4 describes crosstalk between sumoylation and ubiquitination, two similar but distinct post-translational modifications that act in concert to regulate the proteasomal degradation of a subset of protein targets. Chapter 5 shows that sumoylation of HIF-2_ marks it for proteasomal degradation during hypoxia, facilitated by E3 ubiquitin ligases RNF4 and VHL. Chapter 6 presents data on the formation of SUMO chains made up of a mix of SUMO-1 and SUMO-2/3 and we show that HIF-1_ is a target for SUMO chains in vitro. Chapter 7 provides a summary and overall discussion of the thesis.