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Query: UNIPROT:P04637 (
p53
)
77,613
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:p53-mediated apoptosis requires inositol hexakisphosphate kinase-2. 2107 64
The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates
p53
and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase-2 (
IP6K2
), one of the major inositol pyrophosphate synthesizing enzymes, mediates
p53
-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves
IP6K2
destabilization. CK2 physiologically phosphorylates
IP6K2
at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of
IP6K2
are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of
IP6K2
enhances its ubiquitination and subsequent degradation.
IP6K2
mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable.
...
PMID:Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. 2126 46
The apoptotic actions of
p53
require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which
IP6K2
has been implicated in
p53
-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and
p53
. We demonstrate that IP7, formed by
IP6K2
, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates
p53
phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.
...
PMID:Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. 3282 81
The inositol pyrophosphates 5-InsP
7
(diphosphoinositol pentakisphosphate) and 1,5-InsP
8
(bis-diphosphoinositol tetrakisphosphate) are highly energetic cellular signals interconverted by the diphosphoinositol pentakisphosphate kinases (PPIP5Ks). Here, we used CRISPR to KO PPIP5Ks in the HCT116 colon cancer cell line. This procedure eliminates 1,5-InsP
8
and raises 5-InsP
7
levels threefold. Expression of
p53
and p21 was up-regulated; proliferation and G1/S cell-cycle transition slowed. Thus, PPIP5Ks are potential targets for tumor therapy. Deletion of the PPIP5Ks elevated [ATP] by 35%; both [ATP] and [5-InsP
7
] were restored to WT levels by overexpression of PPIP5K1, and a kinase-compromised PPIP5K1 mutant had no effect. This covariance of [ATP] with [5-InsP
7
] provides direct support for an energy-sensing attribute (i.e., 1 mM
K
m
for ATP) of the 5-InsP
7
-generating inositol hexakisphosphate kinases (IP6Ks). We consolidate this conclusion by showing that 5-InsP
7
levels are elevated on direct delivery of ATP into HCT116 cells using liposomes. Elevated [ATP] in
PPIP5K
-/-
HCT116 cells is underpinned by increased mitochondrial oxidative phosphorylation and enhanced glycolysis. To distinguish between 1,5-InsP
8
and 5-InsP
7
as drivers of the hypermetabolic and
p53
-elevated phenotypes, we used
IP6K2
RNAi and the pan-IP6K inhibitor,
N
2-(
m
-trifluorobenzyl),
N
6-(
p
-nitrobenzyl) purine (TNP), to return 5-InsP
7
levels in
PPIP5K
-/-
cells to those of WT cells without rescuing 1,5-InsP
8
levels. Attenuation of IP6K restored
p53
expression but did not affect the hypermetabolic phenotype. Thus, we conclude that 5-InsP
7
regulates
p53
expression, whereas 1,5-InsP
8
regulates ATP levels. These findings attribute hitherto unsuspected functionality for 1,5-InsP
8
to bioenergetic homeostasis.
...
PMID:KO of 5-InsP
7
kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype. 2907 69
Inositol hexakisphosphate kinase 2 (
IP6K2
) potentiates pro-apoptotic signalling and increases the sensitivity of mammalian cells to cytotoxic agents. Diphosphoinositol pentakisphosphate kinase (PPIP5K) generates inositol pyrophosphates (InsPPs) that are structurally distinct from those produced by
IP6K2
and their possible roles in affecting cell viability remain unclear. In the present study, we tested the impact of PPIP5K1 on cellular sensitivity to various genotoxic agents to determine if PPIP5K1 and
IP6K2
contribute similarly to apoptosis. We observed that PPIP5K1 overexpression decreased sensitivity of cells toward several cytotoxic agents, including etoposide, cisplatin, and sulindac. We further tested the impact of PPIP5K1 overexpression on an array of apoptosis markers and observed that PPIP5K1 decreased
p53
phosphorylation on key residues, including Ser-15, -46, and -392. Overexpression of a kinase-impaired PPIP5K1 mutant failed to protect cells from apoptosis, indicating this protection is a consequence PPIP5K1 catalytic activity, in contrast with the sensitivity conferred by
IP6K2
, which is dependent on both catalytic and non-catalytic functions. These observations reveal distinct roles for PPIP5K1 and
IP6K2
and the InsPPs they produce in controlling cell death.
...
PMID:PPIP5K1 Suppresses Etoposide-triggered Apoptosis. 3105 Oct 14
