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

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 inositol 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 p300, 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 inositol phosphates, acting as the rate-limiting enzyme in generation of inositol pentakisphosphate and thus of higher inositol phosphates, especially the energetic inositol pyrophosphates (Fig. 1A). Recently, Watson et al. described a potential role for IP4 (1,4,5,6) in the activation of HDAC3. IPMK is also a major PI3 kinase, which acts together with the wortmannin-sensitive p110/p85 PI3 kinase to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) that activates Akt and protein synthesis. Interestingly, IPMK also displays physiologic roles independent of its catalytic activity. Both wild-type and catalytically inactive IPMK stabilize the mTOR-1 complex to facilitate protein translation. Hints that IPMK might have a transcriptional function stemmed from the Gene transcription by p53 requires inositol polyphosphate multikinase as a co-activator