Develop drug therapies based on insights into the proteasome.

Dr. Finley’s studies investigating the enzymatic and non-enzymatic activities associated with the proteasome that modulate the recognition of ubiquitinated conjugates, the regulation of the balance of protein degradation with deubiquitination, and the temporal sequence of ubiquitin conjugate destruction, lend themselves to drug development and the elucidation of novel molecular drug targets. Many diseases, such as cancer and Huntington’s disease, have prominent aberrations in protein turnover. Moreover, a marketed drug approved for treating multiple cancers works through disruption of proteasome activity, although it has toxicity issues. Thus, there is a plausible rationale for uncovering components of the proteasome that may be considered as the basis for creating drugs. These drugs could potentially lead to improved therapies that preferentially target diseased tissues with aberrant protein turnover or proteasome activity. The fact that several layers of regulation appear to control the proteasome output suggests that there are as-yet uncharacterized targets amenable to drug therapy.
 

• Investigate the recognition parameters employed by the proteasome for ubiquitin conjugates, focusing on intrinsic proteasome subunits, as well as ancillary proteins displaying transient interactions with the proteasome.
   
• Extend studies on the negative regulation of the proteasome mediated by Ubp6/Usp14, investigating its enzymatic and non-enzymatic functions, as well as its regulation by other molecules.
   
• Explore the functional consequences of subunit communications that may comprise transient contacts, stable physical associations, and so on, such as the interaction between Ubp6 and Hul5.
   
• Discern metabolic signaling mechanisms that maintain adequate proteasome activity during stress.
   
• Study the transcriptional control of the proteasome subunits as it relates to normal physiology and to the etiology of various diseases.
   
• Investigate the role of the proteasome in diseases characterized by protein misfolding or ultrastable oncoproteins (that is, proteinopathies).
   

Dr. Finley’s laboratory published groundbreaking studies into the intricate workings of proteasome-dependent protein degradation, with a focus on the proteasome itself. The laboratory employed genetic and biochemical approaches to gain insights into the proteasome’s 35-plus component structure, the assembly, and the mechanics (both enzymatic and non-enzymatic) of this biological machine, which is critical for cellular homeostasis. These recent studies have capitalized on yeast genetics to facilitate the interrogation of proteasome activities and the cellular mechanisms that integrate the proteasome activities into the cellular metabolic equilibrium. The lab’s studies on the deubiquitinating enzyme Ubp6 (the human ortholog is Usp14) uncovered multiple activities for this tightly associated component of the proteasome. Elegant studies demonstrated  that Ubp6 is adept at stalling the catabolism of ubiquitinated substrates, thus curbing proteasome activity. This activity does not involve its deubiquitinating enzymatic activity, demonstrating that Ubp6 possesses dual functions that work together to counterbalance protein degradation. The laboratory also found that Ubp6 is important for cementing the Hul5 ubiquitin ligase to the proteasome complex.

Other experiments have shown that the architectural integrity of the proteasome, consisting of a regulatory and core particle, is preserved by specific molecules, as well as the process of protein degradation itself. The laboratory has also investigated proteasome activity in cells undergoing a stress response. The lab found that effective regulatory constraints are operable for maintaining proteasome levels and perturbations in ubiquitin levels, which trigger a stress response, lead to an altered composition of proteasomal subunits rather than increases in the number of proteasome complexes, as is observed following proteasome stress. 

Biological Mechanisms and Pathways

• Core particle •
• Deubiquitination •
• Non-catalytic activity •
• Oncology •
• Proteasome •
• Proteasome •
• Proteasome •
• Protein degradation •
• Protein interactions •
• Protein misfolding •
• Stress response •
• Ubiquitin conjugate •
• Ubiquitin ligase •
• Ubiquitination •
• Ubp6
•  

Cancer

• Cancer •
• Oncology
•  

Disease Mechanisms

• Cancer •
• Proteinopathy
•  

Research Tools and Instrumentation

• Mammalian cells •
• Yeast
•  

Therapeutic Discovery Tools and Assays

• Cancer •
• Mammalian cells •
• Yeast
•