Abstract
We report that prosaposin treatment induced extracellular signal-regulated kinases (ERKs) and sphingosine kinase activity, increased DNA synthesis, and prevented cell apoptosis. Prosaposin treatment induced pheochromocytoma cells (PC12) to enter the S phase of the cell cycle; this effect was inhibited by the MEK inhibitor PD98059, indicating that prosaposin-induced ERK phosphorylation is required for stimulation of DNA synthesis. The prosaposin effect was also inhibited by pertussis toxin, indicating that the prosaposin receptor is a G-protein-coupled receptor. Prosaposin rescued PC12 cells from apoptosis induced by staurosporine or ceramide. Sphingosine kinase activity was increased by prosaposin treatment. We propose that this effect is a mechanism underlying the proliferative and anti-apoptotic functions of prosaposin. Prosaposin appears to be a key regulatory factor in the ceramide-S-1-P rheostat, which regulates cell fate.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adrenal Gland Neoplasms
-
Animals
-
Apoptosis / drug effects*
-
Cell Cycle / drug effects*
-
Cell Cycle / physiology
-
DNA, Neoplasm / biosynthesis
-
Enzyme Activation / drug effects
-
Enzyme Inhibitors / pharmacology
-
Flavonoids / pharmacology
-
G1 Phase
-
Glycoproteins / pharmacology*
-
Milk
-
Mitogen-Activated Protein Kinases / metabolism*
-
PC12 Cells
-
Pertussis Toxin
-
Pheochromocytoma
-
Phosphotransferases (Alcohol Group Acceptor) / metabolism*
-
Protein Precursors / pharmacology
-
Rats
-
Resting Phase, Cell Cycle
-
Saposins
-
Sphingolipids / metabolism
-
Virulence Factors, Bordetella / pharmacology
Substances
-
DNA, Neoplasm
-
Enzyme Inhibitors
-
Flavonoids
-
Glycoproteins
-
Protein Precursors
-
Psap protein, rat
-
Saposins
-
Sphingolipids
-
Virulence Factors, Bordetella
-
Pertussis Toxin
-
Phosphotransferases (Alcohol Group Acceptor)
-
sphingosine kinase
-
Mitogen-Activated Protein Kinases
-
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one