MODULATION OF CERAMIDE-ACTIVATED PROTEIN PHOSPHATASE 2A ACTIVITY BY LOW-MOLECULAR-WEIGHT AROMATIC-COMPOUNDS

Protein phosphatase 2A (PP2A) is one of the most important and abundan t serine/threonine phosphatases in mammalian tissues and plays a role in gene expression, cell division, and signal transduction. PP2A is ac tivated by ceramide, which is produced by the hydrolysis of membrane s phingomyelin in response to a variety of stress-related stimuli. To fu rther study the role of ceramide-mediated signal transduction in cellu lar processes such as senescence and apoptosis, we designed and synthe sized a series of low molecular weight aromatic compounds, mainly of t he isoquinolone and tetralone classes, and evaluated their ability to inhibit enzymes known to be activated by ceramide. Those enzymes studi ed were ceramide-activated protein kinase, protein kinase C zeta and P P2A. Oi these, only PP2A was found re, be inhibited. A few of the comp ounds inhibited both ceramide-activated as well as basal PP2A activity . In addition, several of the compounds activated PP2A by up to 300% a bove basal enzyme activity, but only in the presence of ceramide. Thus , modulation (both inhibition and activation) of the catatylic activit y of ceramide-activated PP2A is demonstrated by certain low molecular weight aromatic compounds. (C) 1998 Elsevier Science Inc.