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Ceramide is a major sphingolipid with sphingosine
as its basic structure. We reported in 1989 that ceramide increased
intracellularly during the growth inhibition period in cell differentiation,
and exogenous cell-permeable synthetic ceramide is known to induce
cell differentiation.1),2)
Since then, ceramide has been further recognized as a signal-transducing
molecule in cell death and survival. Ceramide is degraded with
ceramidase to sphingosine, which is then phosphorylated by sphingosine
kinase to form sphingosine-1-phosphate (S1P).3)
The chemotactic effect of S1P and its platelet aggregation action
induced by its release from platelets were reported for the first
time by Igarashi et al.,4)
and the association with fibroblast proliferation and calcium
increase were reported by Spiegel et al..5)
S1P is attracting more attention for its intracellular signaling
functioning in cell survival and during cell growth, rather than
simply as an intracellular.
The amount of ceramide within cells is regulated by intracellular
production and degradation, which is induced by various stresses
and controlled by ceramide-associated enzymes such as sphigomyelinase
(SMase), ceramidase, glucosylceramide synthase (GCS) and sphingomyelin
synthase (SMS), as shown in Fig. 1.
On the other hand, S1P degradation is regulated by S1P lyase
and phosphoproteinphosphatase. Intracellular ceramide induces
the capase family and reactive oxygen intermediates (ROI), which
are signals for inducing apoptosis, whereas S1P is known to extracellularly
activate the phosphatidylinositol 3-kinase (PI-3) pathway through
G-protein-binding endothelial differentiation gene (EDG) family
receptors.4) The
interaction of ceramide with S1P on cell function was reported
in 1996, i.e., S1P enhances the activation of protein kinase
C, which leads to the inhibition of ceramide-induced apoptosis.6) Our studies showed
that ceramide-induced apoptosis is activated via inhibition of
PI-3 activity/ Akt kinase activity, and that PI-3 potentiates
inhibition of sphigomyelinase (SMase) activity and subsequently
inhibits the ability to produce intracellular ceramide in response
to stress,7),8)
as shown in Fig. 2. Furthermore,
recent findings identified the EDG family as the receptors for
S1P intercellular reaction and also showed that PI-3 activity,
which is induced via G-protein-binding phospholipase C activation,
to be an important factor in the S1P downstream signal. These
findings suggest that PI-3 may play an important role in controlling
the interaction signal of ceramide and S1P.8)
In addition, preliminary studies show that ceramide binds to
and regulates directly PI-3 intracellularly and that ceramide
may control the cell proliferation signals downstream.9)
From the above, sphingolipid, ceramide and S1P
function interdependently and are deeply correlated with cell
proliferation, cell survival and induction of apoptosis.5) Their interaction in
the mechanism of maintaining a microdomain structure on the cell
membrane is also becoming a subject of recent interest.10) |
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| References |
(1) |
Okazaki T, Kondo T, Kitano T, Tashima M: Diversity and complexity
of ceramide signalling in apoptosis. Cell Signal. 10,
685-692, 1998 |
|
(2) |
Obeid LM, Hannun YA: Ceramide, stress, and a "LAG"
in aging. Sci Aging Knowledge Environ. PE27, 2003 |
|
(3) |
Spiegel S, Milstien S: Sphingosine-1-phosphate: an enigmatic
signalling lipid. Nat Rev Mol Cell Biol. 4, 397-407, 2003 |
|
(4) |
Igarashi Y: Current studies on a novel lipid mediator, sphingosine
1-phosphate, and its receptors. Tanpakushitsu Kakusan Koso,
47, 476-479, 2002 |
|
(5) |
Perry DK, Kolesnick RN: Ceramide and sphingosine 1-phosphate
in anti-cancer therapies. Cancer Treat Res. 115, 345-354,
2003 |
|
(6) |
Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind
S, Spiegel S: Suppression of ceramide-mediated programmed cell
death by sphingosine-1-phosphate. Nature. 381, 800-803,
1996 |
|
(7) |
Kondo T, Kitano T, Iwai K, Watanabe M, Taguchi Y, Yabu T,
Umehara H, Domae N, Uchiyama T, Okazaki T: Control of ceramide-induced
apoptosis by IGF-1: involvement of PI-3 kinase, caspase-3 and
catalase. Cell Death Differ. 9, 682-692, 2002 |
|
(8) |
Kondo T, Okazaki T: Crosstalk between ceramide and phosphatidylinositol-3
kinase as a mechanism for cell death/survival determination.
Tanpakushitsu Kakusan Koso, 47, 442-448, 2002 |
|
(9) |
Okazaki T, Ito M: Signal transduction of ceramide. Tanpakushitsu
Kakusan Koso, 47, 438-441, 2002 |
|
(10) |
Gulbins E, Kolesnick R: Raft ceramide in molecular medicine.
Oncogene, 22, 7070-7077, 2003 |
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