Lysophosphatidic acid induces upregulation of Mcl-1 and protects apoptosis in a PTX-dependent manner in H19-7 cells.

Lysophosphatidic acid (LPA) is a lipid growth factor known to regulate diverse cell functions, including cell proliferation, survival, and apoptosis. Tight regulation of cell survival in neuronal precursor is essential during neurogenesis in both developing and adult brain. Increasing data show that diverse external factors including LPA play roles in controlling cell survival and apoptosis in early developing neurons. However, the underlying control mechanism remains unclear. To explore how LPA regulates cell survival or apoptosis in a developing neuron, mechanisms for cell survival and signaling cascades by LPA were investigated in H19-7 hippocampal progenitor cells. Here, we showed that LPA promotes cell survival by protection from apoptosis. Mcl-1 was demonstrated to be crucial in LPA-induced cell survival by transfection of the siRNA specific for Mcl-1 and overexpression of Mcl-1. LPA-induced cell survival was critically mediated by the upregulation of Mcl-1 which was regulated not only through a post-translational control but a transcriptional control. Mcl-1 stabilization by LPA-induced inhibitory phosphorylation of GSK-3 contributed predominantly to the Mcl-1 upregulation. Both LPA-induced cell survival and the GSK-3 phosphorylation were attenuated by PTX and by siRNA specific for LPA1 or LPA2 receptor. Taken together, these results showed that Mcl-1 stabilization by inhibitory phosphorylation of GSK-3 through Gi/o coupling of the LPA1 and LPA2 receptors following Mcl-1 upregulation plays a critical role in LPA-induced survival of H19-7 cells. In developing neurons, modulation of Mcl-1 levels may constitute a crucial mechanism for controlling their fates.