The Ubiquitin Proteasome System (UPS) in Tumour Management and Drug Discovery
Ubiquitin is a polypeptide that is tagged on to various proteins to signal a range of biological processes. The ubiquitin system plays a pivotal role in the regulation of various cellular processes including protein degradation, DNA damage repair, and signal transduction. The process of ubiquitination involves a cascade of enzymes, E1, the activating enzyme, E2 (conjugating enzymes) and E3 (ligases). Characterisation of the ubiquitination process of key proteins that impact on stems cells, immune cells, and cancers is vital to identify therapeutic targets which may influence disease progression and prognosis. The ubiquitin system is compromised in the majority of cancers and is the focus of research by Dr Yi Sheng of York University.
1- Ubiquitin and Ubiquitin Conjugation
Ubiquitin is a small protein that is attached to other proteins in the cell to signal a specific biological process. This is a reversible process that is used to alter the function of the proteins in various ways. The process of attaching ubiquitin to another protein is termed ubiquitination, a highly regulated, sequential, multi-step conjugation process.
Single ubiquitin molecules can be attached to proteins, a process known as monoubiquitinylation and which is associated with various biological processes. However, ubiquitin itself can be ubiquitinylated to form polyubiquitin structures, effectively chains of ubiquitin attached to an initial target protein. The length and specific linkages used between the ubiquitin molecules indicate vastly different biological outcomes for the targeted protein.
Maintaining the balance in this dynamic, complex system requires not only the ability of enzymes to target ubiquitin to substrate proteins but to also remove ubiquitin. Removal of ubiquitin is facilitated by ubiquitin-specific proteases which catalyse the cleavage of ubiquitin from the protein.
2- p53 and Ubiquination Control of Tumourigenesis
p53 is a protein that is known to be a tumour suppressor. It plays a pivotal role in safeguarding the integrity of the genome and preventing tumourigenesis, the development and progression of cancer cells. p53 achieves this by preventing the proliferation of damaged cells, which occurs through one of two key mechanisms. More specifically, by stopping the cell cycle (termed cell cycle arrest) or by inducing programmed cell death (also known as apoptosis). In normal cells, the level of p53 is closely regulated. Regulation is managed by a group of enzymes called E3 ligases. These enzymes drive the ubiquitination of p53 by attaching the small protein, ubiquitin, to p53. This process signals that the tagged p53 should be degraded.
MDM2, an important human E3-ubiquitin-protein ligase, is overexpressed in a number of human malignancies, and as such, it is an attractive target for novel cancer therapies. From a potential therapy perspective, inhibition of the E3 ligase MDM2 in tumours should result in an increase of p53 and subsequently increased levels of p53-activated cell death in cancers that are overexpressing MDM2.
In the past decade, the number of E3 ligases identified by researchers has increased substantially to include Pirh2, COP1, TOPORS and HUWE1 (also known as Mule or ARF-BP1). This broad range of E3 ligases results in greater complexity of the p53-ubiquitylation pathway and offers an increased number of potential drug targets in p53-dependent cancers.
Dr Yi Sheng and her colleagues have studied a number of E3 ligases associated with p53 degradation, with the most commonly known MDM2 protein to identify differences as well as similarities in the structures and functions that may be exploited to inform novel targets for cancer drug therapies.
3- Regulation of the Wnt Pathway
Another pathway which is regulated by ubiquitination is the Wnt pathway, which is key in both embryonic development and maintenance of homoeostasis in adult tissues. Two of the most important pathways managed by the Wnt pathway are cell proliferation and stem cell self-renewal. Genetic manipulation or failed modulation of the Wnt pathway contributes to cancer development in a number of tissues.
\beta-catenin is an important protein which regulates gene transcription. Specifically, it is the intracellular signal transducer in the Wnt signalling pathway. Mutation or overexpression of \beta-catenin is associated with many cancers. In turn, \beta-catenin is regulated and destroyed by a UPS dependent protein complex.
Contributing to the mechanistic research on the regulation of \beta-catenin stability, Dr Sheng and her team’s research has demonstrated that in conditions of high Wnt signalling, an E3 ubiquitin ligase HUWE1 (aka Mule or ARF-BP1) targets \beta-catenin, in collaboration with the Tak Mak lab. This targeting leads to biological degradation, which in turn stops the activation of Wnt signalling. The work demonstrates that a loss of HUWE1 under conditions of hyperactive Wnt signaling promotes the conversion of some stem cells into cancer stem cells, initiating cancer development.
This knowledge offers a number of intervention points for the manipulation of ‘Mule’, \beta-catenin and the Wnt pathway functions to impact on the initiation of tumours.
4- The Role of Ubiquitin in Epigenetic Regulation
The ubiquitin system plays a pivotal role in the epigenetic regulation of many cellular processes such as gene expression, DNA replication, and DNA damage repair (DDR). Dr. Yi Sheng focuses on the study of the ubiquitin system and its role in epigenetic regulation. The work involves investigating molecular mechanisms underlying histone ubiquitination and its coordination with other forms of post-translational modifications (PTMs) in the modulation of chromatin structure and function.
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