Acid sphingomyelinase mediated release of ceramide is essential to trigger the mitochondrial pathway of apoptosis by galectin-1.
The mechanism of apoptosis induced by human galectin-1, a mammalian beta-galactoside-binding protein with a remarkable cytotoxic effect on activated peripheral T cells and tumor T cell lines has been extensively investigated in this study. Here we first show that galectin-1 initiate the acid sphingomyelinase mediated release of ceramide and this event is critical in the further steps. Elevation of ceramide level coincides with exposure of phosphatidylserine on the outer cell membrane. The downstream events, decrease of Bcl-2 protein amount, depolarization of the mitochondria and activation of the caspase 9 and caspase 3 depend on production of ceramide. All downstream steps, including production of ceramide, require the generation of membrane rafts and the presence of two tyrosine kinases, p56(lck) and ZAP70. Based on our findings we suggest a model of the mechanism of galectin-1 triggered cell death.
Ion
Gabriela
G
Lymphocyte Signal Transduction Laboratory, Institute of Genetics, Biological Research Center of Hungarian Academy of Sciences, 62 Temesvari krt, H-6726 Szeged, Hungary.
Fajka-Boja
Roberta
R
Kovács
Ferenc
F
Szebeni
Gábor
G
Gombos
Imre
I
Czibula
Agnes
A
Matkó
János
J
Monostori
Eva
E
D017209:Apoptosis; D002460:Cell Line; D002518:Ceramides / Q000096:biosynthesis*; D037483:Galectin 1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
D002518:Ceramides; D037483:Galectin 1; D014443:Tyrosine; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D013108:Sphingomyelin Phosphodiesterase