Involvement of sphingolipids metabolites in cellular proliferation modulated by ganglioside GM1.
Glycoconj J
; 13(6): 937-45, 1996 Dec.
Article
em En
| MEDLINE
| ID: mdl-8981085
ABSTRACT
The B subunit of cholera toxin, which binds specifically to ganglioside GM1, is mitogenic for quiescent Swiss 3T3 fibroblasts. Recently, sphingolipids metabolites, ceramide, sphingosine and sphingosine-1-phosphate, have been implicated as second messengers in cell growth regulation and differentiation. In this paper, we examined the possibility that interaction of the B subunit with membrane GM1 leads to alterations in metabolism of glycosphingolipids and that increased levels of sphingolipids metabolites may mediate the biological effects of the B subunit. While the B subunit did not induce a change in the level of ceramide or sphingosine, the level of sphingosine-1-phosphate was rapidly and transiently increased. The B subunit also transiently activated cytosolic sphingosine kinase activity, which catalyzes the phosphorylation of the primary hydroxyl group of sphingosine to produce sphingosine-1-phosphate. To determine whether the increase in sphingosine-1-phosphate level plays a role in B subunit-induced mitogenicity, we used a competitive inhibitor of sphingosine kinase, D,L-threo-dihydrosphingosine. D,L-thereo-Dihydrosphingosine not only inhibited B subunit-induced DNA synthesis by 26%, it also reduced its ability to stimulate DNA-binding activity of the transcription factor AP-1. This sphingosine kinase inhibitor also inhibited B subunit-induced increases in the activity of cell cycle-regulated, cyclin-dependent serine/threonine kinases, cdk2 and p34cdc2. These findings suggest that sphingosine-1-phosphate may play a role in the signal transduction pathways activated by binding of the B subunit to endogenous ganglioside GM1.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esfingolipídeos
/
Lisofosfolipídeos
/
Divisão Celular
/
Quinases relacionadas a CDC2 e CDC28
/
Gangliosídeo G(M1)
Idioma:
En
Revista:
Glycoconj J
Assunto da revista:
BIOQUIMICA
/
METABOLISMO
Ano de publicação:
1996
Tipo de documento:
Article
País de afiliação:
Estados Unidos