Current Pharmaceutical Design - Volume 19, Issue 18, 2013

The ubiquitin-proteosome system (UPS) regulates a wide range of cellular processes including protein degradation, DNA repair, transcription regulation, and cell signaling. Alterations and mutations in UPS components give rise to various human diseases, most prominently cancer and neurodegenerative disorders. Here, we review recent advances in UPS-based drug discovery highlighting the emerging relationships bet Read More

The proteasomal pathway of protein degradation involves two discrete steps: ubiquitination and degradation. Blocking protein degradation by inhibiting the proteasome has well described biologic effects and proteasome inhibitors are approved for the treatment of multiple myeloma and mantle cell lymphoma. In contrast, the biological effects and potential therapeutic utility of inhibiting the ubiquitination cascade and the i Read More

The Anaphase Promoting Complex (APC) has been characterized to play pivotal roles in regulating the timely cell cycle progression by forming two functionally distinct E3 ubiquitin ligase sub-complexes, APCCdc20 and APCCdh1. Interestingly, recent studies have shown that Cdh1 is functioning as a tumor suppressor whereas Cdc20 may function as an oncoprotein to promote the development and progression of human cancers. In Read More

The ubiquitin-proteasome system (UPS) promotes the timely degradation of short-lived proteins with key regulatory roles in a vast array of biological processes, such as cell cycle progression, oncogenesis and genome integrity. Thus, abnormal regulation of UPS disrupts the protein homeostasis and causes many human diseases, particularly cancer. Indeed, the FDA approval of bortezomib, the first class of general pr Read More

Smad ubiquitylation regulatory factor-1 (Smurf1) is a HECT-type ubiquitin ligase. The role of Smurf1 in cell development and migration, viral autophagy and immune responses has been the subject of intensive study in recent years. Smurf1 regulates multiple biological networks, including TGF-β and BMP signaling pathways, the non-canonical pathway and the Toll-like receptor pathway, and is linked to certain diseases and d Read More

Deubiquitinating enzymes (DUBs) remove ubiquitin and ubiquitin-like modifications from proteins and they have been known to contribute to processes relevant in microbial infection, such as immune responses pathways. Numerous viral and bacterial DUBs have been identified, and activities of several host DUBs are known to be modulated during the infection process, either by a pathogen or by a host. Recently ther Read More

Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p Read More

During the last two decades, the studies on ubiquitination in regulating transcription factor NF-κB activation have elucidated the expanding role of ubiquitination in modulating cellular events by non-proteolytic mechanisms, as well as by proteasomal degradation. The significance of ubiquitination has also been recognized in regulating gene transcription, epigenetic modifications, kinase activation, DNA repair and sub Read More

Muscle wasting is a prevalent and disabling condition in chronic disease and cancer and has been associated with increased mortality and impaired efficacy of surgical and medical interventions. Pharmacological therapies to combat muscle wasting are currently limited but considered as an important unmet medical need. Muscle wasting has been attributed to increased muscle proteolysis, and in particular ubiquitin 26S-prot Read More

The proteasome inhibition has been proved to be effective in the treatment of multiple myeloma and other malignancies. In addition to direct antitumor effects, proteasome inhibition also exerts strong effects on immune cells, such as T cells, B cells and DCs. Therefore, proteasome inhibition, through the utilization of small molecule drugs like bortezomib, could be used therapeutically to modulate immune responses i Read More

Neurodegenerative diseases are severe disorders characterized by progressive neurodegeneration in specific brain regions. The ubiquitin-proteasome system (UPS) is closely linked to neurodegenerative disease. In most cases, UPS impairment and dysregulation of the UPS components are frequently observed. Moreover, toxin-induced neurodegeneration produces neuronal cell death accompanied by decreased UPS fun Read More

Alterations of the ubiquitin proteasome system (UPS) contribute to the progression of many diseases, such as cancer, neurodegenerative diseases, immunological disorders, and inflammation. Pharmacologic inhibition of specific ubiquitin regulatory enzymes and ubiquitination events is an important challenge in drug discovery. Identifying the substrates of the various enzymes that participate in the UPS is needed to determi Read More

Prostate cancer is a critical public health problem in USA and Europe. New non-invasive imaging methods are urgently needed, due to the low accuracy and specificity of current screen methods and the desire of localizing primary prostate cancer and bone metastasis. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) are the non-invasive and sensitive imaging methods whic Read More

Ultrasound-based multimodal molecular imaging and functional ultrasound contrast agents (UCAs) have garnered great interest in biomedical imaging over the past few years. With the rapid development of molecular imaging technique, UCAs with singlefunction and single imaging modality can no longer satisfy increasingly growing medical diversification and hominization demand. The device of functional UCAs incl Read More