Petroski, Matthew. 2008. The Ubiquitin System, Disease and Drug Discovery. Accessed March 29th 2013. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582801/
THE UBIQUITIN SYSTEM, DISEASE AND DRUG RECOVERY
The ubiquitin system, as its name suggests, controls a host of cellular processes via activation of ubiquitin(UB) by ubiquitin-activating enzyme, its subsequent transfer to the active sites of ubiquitin-conjugating enzymes. Ubiquitin ligases as well as, deubiquilating enzymes, have vital roles in the system which involves the upregulation/downregulation of proteins, apoptosis-inducing effects, proofreading of protein sequences, signalling, receptor function amongst a vast array of other functions that ultimately result in the control of physiological mechanisms at a cellular level and therefore, the homeostatic control of bodily function as well as disease susceptibility and control.
The role of UB in cancer regulation has a pathway in the activity of P53(a transcription factor) which binds to a regulator known as MDM2. Mutations in the P53 gene is known to be present in more than half of all tumours; the binding of MDM2 to P53 occurs via a UB ligase, and is responsible for its target degradation by proteasome.
Cullin-RING ubiquitases have effects on the eukaryotic cell cycle. The VHL (von Hippel-Lindau) gene is a tumour suppressant and the protein encoded for by this gene serves as a substrate receptor for an isotype of UB ligase; mutations in VHL are associated with lung cancer and renal carcinomas. The studies have also found that the mutations in genes coding for a complex known as BRCA1 show predisposition for breast and ovarian cancers. The complex associates with another protein and has UB ligase activity. Ubiquitylation of certain substrates by BRCA1 occurs in some instances, and therefore instead of directing their degradation, the G2/M transition phase of the cell cycle is regulated.
Viruses harness the activity of the ubiqutin system to enable replication and immune system aversion. For example, two proteins encoded by HIV known as VIF and VPU, associate with UB ligases to promote ubiquitylation of cellular proteins. VPU in particular downregulates the expression of the CD4 cell receptor , which is itself a receptor for entry of HIV particles. The effect of this is to block entry of more particles and allow replication of progeny before facilitating their efficient release.
Defects in the UB system also results in metabolic disorders such as diabetes. UB regulates the stability of insulin receptor substrate (IRS) proteins, which themselves are vital in signalling mechanisms. A type of IRS known as IRS2 serves to enhance the growth of pancreatic beta cells which produce insulin. Muscle atrophy disorders have a basis in UB dependent degradation. Upregulation of a variety of genes from the UB system occurs that promote muscular atrophy associated with disease, injury or aging.
Therapeutic indications involving the UB system typically targets the P26 proteasome; the drug for this purpose is known as Velcade was approved by the FDA in 2003 for the treatment of refracted multiple myeloma. The drug itself is a reversible inhibitor of the P26 proteasome. Development of other drugs that manipulate the ubiquitin system is ongoing and focuses on developing inhibitors that target other activity of the proteasome, identifying other targets within the UB system and expanding the indications of proteasome inhibition.
This particular journal was extremely interesting as it served to enlighten the vast role of the UB system and the basis for a wide array of diseases that are detrimental to large swathes of the human population. Explanation of pathways and activity, basis for drug research as well as causation of disease through mutations and cellular activity modification proved an invigorating read that was immensely informative.