Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
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Target Concepts:
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Query: UNIPROT:P04637 (
p53
)
77,613
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
