Protein kinase C activator bryostatin‐1 modulates proteasome function

AbstractProteasome activity in ubiquitin‐proteasome pathway plays a pivotal role in degradation and clearance of aggregated, oxidized, damaged, and misfolded unwanted proteins to control protein homeostasis or proteostasis. Proteasome activity decreases with cellular senescence, aging, and age‐related diseases. Therefore, enhancement of impaired proteasome function by molecular biological and/or pharmacological intervention is an active area of research. Bryostatin‐1, a naturally occurring macrocyclic lactone, activates PKC isozymes (specifically, ‐α and ‐ϵ) at sub‐nanomolar concentrations, but downregulates at higher concentrations. Here, we present bryostatin‐1 increased chymotrypsin‐like proteasome activity of 20S assembly at sub‐nanomolar to nanomolar concentrations (0.3‐30 nM). However, proteasome activity decreased at a micromolar concentration of bryostatin‐1 (AG08044 cultured skin: P < 0.005; differentiated SH‐SY5Y cells: P < 0.02). Modulation of proteasome function by bryostatin‐1 was studied in six dermal fibroblast primary cell lines developed both from freshly taken biopsies from healthy donors (n = 2) and obtained from well‐characterized cell repositories (n = 4;