PT  - JOURNAL ARTICLE
AU  - Mohamed Machwate
AU  - Sevgi B. Rodan
AU  - Gideon A. Rodan
AU  - Shun-Ichi Harada
TI  - Sphingosine Kinase Mediates Cyclic AMP Suppression of Apoptosis in Rat Periosteal Cells
AID  - 10.1124/mol.54.1.70
DP  - 1998 Jul 01
TA  - Molecular Pharmacology
PG  - 70--77
VI  - 54
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/54/1/70.short
4100  - http://molpharm.aspetjournals.org/content/54/1/70.full
SO  - Mol Pharmacol1998 Jul 01; 54
AB  - Prostaglandin E stimulates bone formation in humans and animals, and increases intracellular cAMP in osteoblastic cells. We found that cAMP inhibits apoptosis in osteoblastic cells, and examined the mechanism of this effect. We report that the cAMP elevating agent, forskolin, increases cell number in the rat periosteal cell line (RP-11), by suppressing apoptosis in a cell type-specific manner. In RP-11, forskolin transiently up-regulates extracellular signal-regulated kinase activity, a known suppressor of apoptosis. PD98059, a selective inhibitor of the extracellular signal-regulated kinase pathway, only partially reverses the antiapoptotic effect of forskolin, which suggests an additional mechanism for cAMP action. We found that forskolin stimulates cytosolic sphingosine kinase (SPK) activity in these cells; in two other osteoblastic cell lines, however, forskolin does not suppress apoptosis. In contrast to the partial opposing effect of PD98059 to forskolin action,N,N-dimethylsphingosine, a specific inhibitor of SPK, completely reverses the antiapoptotic effect of forskolin, and has no effect on apoptosis in the absence of forskolin. These findings show for the first time that cAMP activates SPK in a cell-type-specific manner, and suggest that cAMP suppression of apoptosis in RP-11 periosteal cells is mediated by its stimulation of SPK.