Project Term
–
Cincinnati Children's Hospital Medical Center
Cincinnati, OH
United States
Project Summary
Hypomorphic activity of the E1 ubiquitin enzyme, UBA1, has emerged as a driver of myeloid malignancies. However, how dysregulation of UBA1 perturbs protein homeostasis to promote disease remains unknown. The overall objective of this proposal is to determine how hypomorphic UBA1 activity and compensatory UBA6 expression reshape the ubiquitinome in inflammatory-associated myeloid disease and to identify mechanisms of UBA6 regulation that could define novel therapeutic targets.
Lay Abstract
Proteins are fundamental molecules that control cellular function and maintain the balance of protein production, which is critical for cellular health. Cells harbor a surveillance system to ensure that the balance of proteins in the cells is maintained as disruption to protein levels can result in the onset of disease. A key component of this process is the ubiquitin proteasomal system which controls the amount of protein in the cell by adding a ubiquitin molecule onto proteins to mark them for degradation. When this process is dysregulated, erroneous protein accumulation can result in disease, including cancer. Recent work has shown that a key regulator of ubiquitination, UBA1, is frequently mutated or dysregulated in blood cancer but how alteration to ubiquitination leads to cancer is unknown. Furthermore, the other key regulatory protein in this process, UBA6, is also reduced in these patients but whether this also contributes to onset of protein accumulation and disease is poorly understood. This project will focus on profiling the function of these two proteins in models of blood cancer. The results of these studies will provide the foundation to identify novel protein homeostasis cancer therapeutics.
Program
Grant Subprogram