SPHINGOSYLPHOSPHOCHOLINE, A SIGNALING MOLECULE WHICH ACCUMULATES IN NIEMANN-PICK DISEASE TYPE-A, STIMULATES DNA-BINDING ACTIVITY OF THE TRANSCRIPTION ACTIVATOR PROTEIN AP-1

Sphingosylphosphocholine (SPC) is the deacylated derivative of sphingomyelin known to accumulate in neuropathic Niemann-Pick disease type A. SPC is a potent mitogen that increases intracellular free Ca2+ and free arachidonate through pathways that are only partly protein kinase C-dependent. Here we show that SPC increased specific DNA-binding activity of transcription activator AP-1 in electrophoretic mobility-shift assays, Increased DNA-binding activity of AP-1 was detected after only 13 min, was maximal after 6 hr, and remained elevated at 12-24 hr, c-Fos was found to be a component of the AP-1 complex, Northern hybridization revealed an increase in c-fos transcripts after 30 min, Since the increase in AP-1 binding activity preceded the increase in c-fos mRNA, posttranslational modifications may be important in mediating the early SPC-induced increases in AP-1 DNA-binding activity, Western analysis detected increases in nuclear c-Jun and c-Fos proteins following SPC treatment, SPC also transactivated a reporter gene construct through the AP-1 recognition site, indicating that SPC can regulate the expression of target genes, Thus, SPC-induced cell proliferation may result from activation of AP-1, linking signal transduction by SPC to gene expression, Since the expression of many proteins with diverse functions is known to be regulated by AP-1, SPC-induced activation of AP-1 may contribute to the pathophysiology of Niemann-Pick disease.