Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in
phospholipid metabolism occur during cellular differentiation, proliferation, and apoptosis, but the molecular mechanism involved in the above processes remains unknown. We propose that the coordinated expression of different genes responsible for the expression of
transcription factors,
neurotrophins, and
cytokines, along with
lipid mediators generated by the action of
phospholipases A2, C, and D (PLA2, PLC, and
PLD), play a very important role in differentiation, proliferation, and apoptosis. The purpose of this minireview is to discuss recent developments in PLA2, PLC, and
PLD-mediated signaling in the nucleus of LA-N-1
neuroblastoma cell cultures. In brain tissue,
arachidonic acid is mainly released by the action of PLA2 and
phospholipase C/
diacylglycerol lipase (PLC/DAG-
lipase) pathways. We have used LA-N-1 cell cultures to study activities of PLA2, C, and D during
retinoic acid (RA)-mediated differentiation. The treatment of LA-N-1 cells with RA produces an increase in PLA2 activity in the nuclear fraction. This increase in PLA2 activity can be prevented with BMS493, a pan
retinoic acid receptor antagonist, suggesting that RA-induced stimulation of PLA2 activity is a RA receptor-mediated process. The treatment of LA-N-1 cells with 12-O-tetradecanoyl-phorbol-13
acetate (TPA) and RA increases
diacylglycerol (DAG) levels indicating the stimulation of PLC activity. This stimulation is blocked by
D609, tricyclodecan-9-yl
potassium xanthate, a competitive PtdCho-specific PLC inhibitor. LA-N-1 cells also contain DAG-and
monoacylglycerol (MAG)
lipase activities. Two
isoforms of
PLD,
oleate-dependent and TPA-dependent, are also present in LA-N-1 cell homogenates. RA stimulates the
oleate-dependent
isoform of
PLD, whereas RA does not stimulate the TPA-dependent
isoform. Our studies have indicated that
lipid mediators generated by the action of PLA2, PLC, and
PLD on nuclear
phospholipids markedly affect neuritic outgrowth and
neurotransmitter release in cells of neuronal and glial origin. We propose that RA receptors coupled with PLA2, PLC, and
PLD activities in the nucleus may play an important role in the redistribution of
arachidonic acid and its metabolites and DAG in nuclear and non-nuclear neuronal membranes during differentiation and growth suppression.