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Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase

ROBERTA MISASI¹, MAURIZIO SORICE, LUISA DI MARZIO^*, W. MARIE CAMPANA, SABRINA MOLINARI, MARIA GRAZIA CIFONE^*, ANTONIO PAVAN^*, GIUSEPPE M. PONTIERI and JOHN S. O’BRIEN

Dipartimento di Medicina Sperimentale e Patologia, Università ‘La Sapienza’ Roma, Rome, Italy;
^* Dipartimento di Medicina Sperimentale, Università di L’Aquila, Italy; and
Department of Neurosciences, University of California, San Diego, School of Medicine, Center for Molecular Genetics, La Jolla, California, USA

¹Correspondence: Dipartimento di Medicina Sperimentale e Patologia. Università ‘La Sapienza’ Roma, Policlinico Umberto I, Viale Regina Elena 324, Rome, 00161 Italy. E-mail: roberta.misasi{at}uniroma1.it

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., Sorice, M., Di Marzio, L., Campana, W. M., Molinari, S., Cifone, M. G., Pavan, A., Pontieri, G. M., O’Brien, J. S. Prosaposin treatment induces PC12 entry in the S phase of the cell cycle and prevents apoptosis: activation of ERKs and sphingosine kinase.

Key Words: signal-regulated protein kinase • BrdU • S-1-P • PC12 cells

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