The role of inositol signaling in the control of apoptosis

Abstract

Inositol signaling reactions are very broad in scope affecting many cellular functions. In this report we describe experiments showing that two distinct parts of this system play pivotal roles in an important cellular event, namely apoptosis. Apoptosis is important for organ development and also for controlling cell survival after various stresses which include DNA damage and other proapoptotic stimuli such as tumor necrosis factor α. We show that the inositol phosphate InsP6 or one of its pyrophosphate metabolites determines the extent of apoptosis following tumor necrosis factor α treatment whereby increased cellular levels of InsP6 protect from apoptosis and decreased levels promote it. Cellular levels of InsP6 are determined by the activity of 5/6-kinase since this is the rate limiting enzyme in production of the highly phosphorylated inositol phosphates including InsP6. A lipid inositol metabolite PtdIns5P is also critical in regulating the activity of p53-dependent apoptosis. This phospholipid is formed in cells by the action of type I 4-phosphatase on PtdIns(4,5)P2. PtdIns5P stabilizes p53 by promoting its acetylation in complex with the nuclear factor ING2. Upon genotoxic stress type I 4-phosphatase migrates to the nucleus where it catalyzes the formation of PtdIns5P to stabilize p53 and increase apoptosis.