Cell cycle control of PDGF-induced Ca2+ signaling through modulation of sphingolipid metabolism

The effects of growth factors have been shown to depend on the position of a cell in the cell cycle. However, the physiological basis for this phenome non remains unclear. Here we show that the majority of both CEINGE clone3 ( c13) and human embryonic kidney 293 cells, when arrested in a quiescent pha se (G(0)), responded to platelet-derived growth factor BE (PDGF-BB) with no n-oscillatory Ca2+ signals. Furthermore, the same type of Ca response was a lso observed in CEINGE c13 cells (and to a lesser extent in HEK 293 cells) blocked at the G(1)/S boundary. In contrast, CEINGE c13 cells synchronized in early G(1) or released from G(1)/S arrest responded in an oscillatory fa shion. This cell cycle-dependent modulation of Ca2+ signaling was not obser ved on epidermal growth factor and G-protein-coupled receptor stimulation a nd was not due to differences in the expression of PDGF receptors (PDGFRs) during; the cell cycle. We demonstrate that inhibition of sphingosine-kinas e, which converts sphingosine to sphingosine-1-phosphate, caused G(0) as we ll as G(1)/S synchronized cells to restore the oscillatory Ca2+ response to PDGF-BB, In addition, we show that the synthesis of sphingosine and sphing osine-1-phosphate is regulated by the cell cycle and may underlie the diffe rences in Ca2+ signaling after PDGFR stimulation.