Inositol Polyphosphate Multikinase Is a Coactivator of p53-Mediated Transcription and Cell Death

Abstract

The tumor suppressor protein p53 is a critical stress response transcription factor that induces the expression of genes leading to cell cycle arrest, apoptosis, and tumor suppression. We found that mammalian inositol polyphosphate multikinase (IPMK) stimulated p53-mediated transcription by binding to p53 and enhancing its acetylation by the acetyltransferase p300 independently of its inositol phosphate and lipid kinase activities. Genetic or RNA interference (RNAi)–mediated knockdown of IPMK resulted in decreased activation of p53, decreased recruitment of p53 and p300 to target gene promoters, abrogated transcription of p53 target genes, and enhanced cell viability. Additionally, blocking the IPMK-p53 interaction decreased the extent of p53-mediated transcription. These results suggest that IPMK acts as a transcriptional coactivator for p53 and that it is an integral part of the p53 transcriptional complex facilitating cell death.

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

“…2F) and the percentage of metastases to liver (Fig. 2G), the most common site of metastasis for The inositol polyphosphate kinases, including IP6Ks, have both catalytic activity-dependent and -independent functions (1,5,11,27,28). To examine whether the oncogenic actions of IP6K2 depend on its catalytic activity, we established rescue cell lines by retroviral expression of wild-type (WT-R) or kinase-dead K222A IP6K2 (29) (KD-R) in IP6K2 −/− cells.…”

“…IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.…”

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction

“…Whereas IPMK's ability to regulate transcription in yeast is well-established, nuclear roles of mammalian IPMK are less understood. We recently reported that IPMK binds to p53 during cell death and enhances p53-mediated gene transcription independent of IPMK catalytic activity (17,18). Blind et al (23) showed that IPMK's nuclear PI3 kinase activity generating PIP3 is integral to the transcription of steroidogenic factor 1 targets (23).…”

“…In addition, IPMK displays physiologic activities that are independent of its catalytic activity, such as binding and stabilizing the mTOR1 complex (16), as well as enhancing p53-mediated transcription and cell death (17,18). We show that IPMK is a transcriptional coactivator that is required for induction of a multiplicity of IEGs in the brain by binding to and regulating the recruitment of the histone acetyltransferase CBP.…”

Huntington’s disease: Neural dysfunction linked to inositol polyphosphate multikinase

“…Furthermore, IPMK displays functions independent of its kinase activity. It binds and stabilizes the mTOR complex (16) and serves as a transcriptional coactivator for CREB-binding protein (17), p53 (18), and serum response factor (19). Despite these insights into the functions of IPMK, its physiologic and pathologic regulation have been largely unexplored.…”