Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase.
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.
Misasi
R
R
Dipartimento di Medicina Sperimentale e Patologia, Università 'La Sapienza' Roma, Rome, Italy. roberta.misasi@uniroma1.it
Sorice
M
M
Di Marzio
L
L
Campana
W M
WM
Molinari
S
S
Cifone
M G
MG
Pavan
A
A
Pontieri
G M
GM
O'Brien
J S
JS
D000310:Adrenal Gland Neoplasms; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase; D006023:Glycoproteins / Q000494:pharmacology*; D008892:Milk; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016716:PC12 Cells; D037342:Pertussis Toxin; D010673:Pheochromocytoma; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D016192:Resting Phase, Cell Cycle; D049231:Saposins; D013107:Sphingolipids / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D000099157:Sphingosine Kinase
D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006023:Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D037342:Pertussis Toxin; D017853:Phosphotransferases (Alcohol Group Acceptor); D011498:Protein Precursors; D049231:Saposins; D013107:Sphingolipids; D010566:Virulence Factors, Bordetella; D000099157:Sphingosine Kinase; C483347:Psap protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one