p53 välitteinen apoptoosi tarvitsee IP6K2 entsyymiä

 IP6K2 sitoutuu suoraan p53 proteiiniin.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000257/
 LÄHDE:  p53-mediated apoptosis requires inositol hexakisphosphate kinase-2

Michael A. Koldobskiy,^a,b Anutosh Chakraborty et aol. 

Abstract

Inositol pyrophosphates have been implicated in numerous biological processes. Inositol hexakisphosphate kinase-2 (IP6K2), which generates the inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), influences apoptotic cell death. The tumor suppressor p53 responds to genotoxic stress by engaging a transcriptional program leading to cell-cycle arrest or apoptosis. 

We demonstrate that IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. Gene disruption of IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21.

Among the inositol phosphates, inositol 1,4,5-trisphosphate is best known for its release of intracellular calcium (1). The inositol pyrophosphates (IPPs), synthesized by inositol hexakisphosphate kinases (IP6Ks), regulate numerous processes including chemotaxis (2), telomere length (3, 4), endocytic trafficking (5), exocytosis (6), and apoptosis (7, 8).

 The principal inositol pyrophosphate, diphosphoinositol pentakisphosphate (5-PP-IP5), here designated IP7, is generated by three IP6 kinases that are the products of three separate genes (9).

 Another isomer of IP7, 3-PP-IP5, is synthesized by a distinct enzyme, Vip1, and regulates cell shape, growth, and phosphate disposition of yeast (10, 11).

 IP6K1 has been directly implicated in vesicular trafficking and tissue growth, because IP6K1-deleted mice manifest diminished insulin release, slowed growth, and defects in spermiogenesis (12). IP6K2 selectively impacts cell death, because its overexpression sensitizes cells to diverse apoptotic stimuli such as DNA damage, hypoxia, hydrogen peroxide, and interferon-β; knockdown of IP6K2 but not IP6K1 or IP6K3 diminishes sensitivity to such stimuli (7, 8, 13, 14).

 Recently, Lindner and coworkers (15) developed IP6K2 knockout mice that are predisposed to invasive aerodigestive tract carcinoma driven by chemical carcinogenesis, and fibroblasts from the mice resist γ-irradiation. The mechanism by which IP6K2 regulates cell death has not been established. 

We now show that IP6K2 is required for p53-mediated apoptosis and acts by binding p53 and selectively diminishing expression of its pro-cell-cycle arrest targets.