Gene transcription by p53 requires inositol polyphosphate multikinase as a co-activator

摘要

The tumor suppressor p53 is a major transcription factor that induces genes regulating cell cycle arrest and death and which is inactivated in about half of all human cancers. Despite considerable research on p53, mechanisms regulating its activation have not been fully elucidated. We have recently established that the enzyme ino-sitol polyphosphate multikinase (IPMK) is a transcriptional co-activator of p53. Independent of its catalytic activity, IPMK binds p53 and stimulates its binding to the acetyltransferase рЗОО, increasing its acetylation activity, which augments transcriptional activity and p53-associated cell death. IPMK is a remarkably pleiotropic enzyme. Its first characterized enzyme activity involves phosphorylation of inosi-tol phosphates, acting as the rate-limiting enzyme in generation of inositol pen-takisphosphate and thus of higher inositol phosphates, especially the energetic inositol pyrophosphates (Fig. 1A).