Increased Levels of Inositol Hexakisphosphate (InsP6) Protect HEK293 Cells from Tumor Necrosis Factor α- and Fas-induced Apoptosis

Verbsky, John W.; Majerus, Philip W.

doi:10.1074/jbc.m503366200

Cited by 31 publications

(24 citation statements)

References 19 publications

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“…Previous work in mammalian cells demonstrated that IP 6 is protective from apoptosis (41), consistent with our results that loss of IP production leads to increased cell death.…”

supporting

confidence: 82%

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Seeds

Tsui

Sunu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inositol phosphate kinase 2 (Ipk2), also known as IP multikinase IPMK, is an evolutionarily conserved protein that initiates production of inositol phosphate intracellular messengers (IPs), which are critical for regulating nuclear and cytoplasmic processes. Here we report that Ipk2 kinase activity is required for the development of the adult fruit fly epidermis. Ipk2 mutants show impaired development of their imaginal discs, the primordial tissues that form the adult epidermis. Although disk tissue seems to specify normally during early embryogenesis, loss of Ipk2 activity results in increased apoptosis and impairment of proliferation during larval and pupal development. The proliferation defect is in part attributed to a reduction in JAK/ STAT signaling, possibly by controlling production or secretion of the pathway's activating ligand, Unpaired. Constitutive activation of the JAK/STAT pathway downstream of Unpaired partially rescues the disk growth defects in Ipk2 mutants. Thus, IP production is essential for proliferation of the imaginal discs, in part, by regulating JAK/STAT signaling. Our work demonstrates an essential role for Ipk2 in producing inositide messengers required for imaginal disk tissue maturation and subsequent formation of adult body structures and provides molecular insights to signaling pathways involved in tissue growth and stability during development.inositol phosphates | inositol phosphate multikinase | Ipk2 | IPMK | Upd A t the confluence of numerous signaling pathways is phospholipase C (PLC)-mediated production of the second messenger inositol 1,4,5-trisphosphate (IP 3 ), a key regulator of intracellular calcium release (1). IP 3 also serves as an essential substrate for the synthesis of inositol phosphates (IPs) and pyrophosphates (PP-IPs) that are critical for eukaryotic cellular function in their own right (2-6). Phosphorylation of IP 3 by conserved inositol phosphate kinases (IPKs) leads to the synthesis of complex pools of different IP species (6). Insights into the cellular functions of IPs have been gleaned by perturbing their synthesis through genetic manipulations of the IPKs. Consequently, defects in specific cellular processes were attributed to losses of particular IPs. This revealed that IPs are specific regulators of diverse cellular processes, such as transcription, chromatin remodeling, DNA repair, RNA editing, and RNA export (3-7).An essential enzyme for the conversion of IP 3 to the array of IP and PP-IP species found in cells is the evolutionarily conserved inositol phosphate kinase 2 (Ipk2, Fig. 1A), which is also known as IP multikinase (IPMK) (4). Ipk2 was first identified in yeast as a nuclear enriched protein whose activities toward the 6-and 3-positions on the inositol ring sequentially convert IP 3 to IP 4 , and then IP 5 (Fig. 1A) (8-10). Yeast Ipk2 mutants that fail to produce IP 4 and IP 5 exhibit defects in transcriptional responses and chromatin remodeling (3). Additional "multikinase" activities described for certain Ipk2 orthologs indicate an array ...

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“…Previous work in mammalian cells demonstrated that IP 6 is protective from apoptosis (41), consistent with our results that loss of IP production leads to increased cell death.…”

supporting

confidence: 82%

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Seeds

Tsui

Sunu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…An interaction protein of IP6K2, TRAF2 (Morrison et al , 2007 ) also participates in this anti-apoptotic signaling of TNF receptors. Furthermore, Verbsky and Majerus (2005) showed that increased levels of InsP 6 due to its forced biosynthesis protect HEK293 cells from apoptosis derived by TNF-α and they speculated whether pyrophosphorylated inositols might be responsible for the protection (Verbsky and Majerus , 2005 ). These data together might indicate a linkage between TNF-α signaling protein components, DPIPs, and their respective kinases.…”

Section: Future Researchmentioning

confidence: 93%

Synthesis and biological actions of diphosphoinositol phosphates (inositol pyrophosphates), regulators of cell homeostasis

Wundenberg

Mayr

2012

Biological Chemistry

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Diphosphoinositol phosphates are a subclass of inositol phosphates possessing one or two high energy diphosphate groups instead of phosphoester substituents of the myo -inositol. Here we describe the enzymes responsible for their synthesis and degradation and how these may be regulated. Formation of diphosphoinositol phosphates in yeast and mammals is driven by an increase of the cellular energy charge, a lack of inorganic phosphate, and in mammals by osmotic or heat stress and in some cases by receptor mediated signaling. Known cellular actions are an improvement of the cell homeostasis by a reduction of the energy charge, increased phosphate uptake, improvement of mitochondrial performance, and an increase of insulin secretion in mammals. The underlying molecular mechanisms of action are far from being clarifi ed but an increasing body of knowledge about molecular details has highlighted their complex participation in many cellular systems and metabolic processes.

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“…Both the protein kinase Irak2 and adaptor protein Myd88 play key roles in the activation of NFκB [22], whereas Traf3 has been shown to inhibit NFκB activation [23]. The role of the enzyme Ippk is still unclear, but it has been shown to play a role in the inhibition of apoptosis [24]. In addition, c-jun is also up-regulated in comparison to the ISO stimulated nuclei.…”

Section: Targets Of β-Adrenergic Transcriptional Responses In Isolatementioning

confidence: 99%

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

Vaniotis

Duca

Trieu

et al. 2011

Cellular Signalling

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Both β 1 -and β 3 -adrenergic receptors (β 1 ARs and β 3 ARs) are present on nuclear membranes in adult ventricular myocytes. These nuclear-localized receptors are functional with respect to ligand binding and effector activation. In isolated cardiac nuclei, the non-selective βAR agonist isoproterenol stimulated de novo RNA synthesis measured using assays of transcription initiation (Boivin et al., 2006 Cardiovasc Res. 71:69-78). In contrast, stimulation of endothelin receptors, another G protein-coupled receptor (GPCR) that localizes to the nuclear membrane, resulted in decreased RNA synthesis. To investigate the signalling pathway(s) involved in GPCR-mediated regulation of RNA synthesis, nuclei were isolated from intact adult rat hearts and treated with receptor agonists in the presence or absence of inhibitors of different mitogen-activated protein kinase (MAPK) and PI3K/PKB pathways. Components of p38, JNK, and ERK1/2 MAP kinase cascades as well as PKB were detected in nuclear preparations. Inhibition of PKB with triciribine, in the presence of isoproterenol, converted the activation of the βAR from stimulatory to inhibitory with regards to RNA synthesis, while ERK1/2, JNK and p38 inhibition reduced both basal and isoproterenol-stimulated activity. Analysis by qPCR indicated an increase in the expression of 18 S rRNA following isoproterenol treatment and a decrease in NFκB mRNA. Further qPCR experiments revealed that isoproterenol treatment also reduced the expression of several other genes involved in the activation of NFκB, while ERK1/2 and PKB inhibition substantially * Corresponding authors. Hébert is to be contacted

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Increased Levels of Inositol Hexakisphosphate (InsP6) Protect HEK293 Cells from Tumor Necrosis Factor α- and Fas-induced Apoptosis

Cited by 31 publications

References 19 publications

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Inositol phosphate kinase 2 is required for imaginal disc development in Drosophila

Synthesis and biological actions of diphosphoinositol phosphates (inositol pyrophosphates), regulators of cell homeostasis

Nuclear β-adrenergic receptors modulate gene expression in adult rat heart

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