Nuclear inositides: PI-PLC signaling in cell growth, differentiation and pathology.

The existence of phospholipids in chromosomes has been suggested by the work of La Cour et al. (1958). In the 1970s, Manzoli and colleagues demonstrated that addition of phospholipids to purified nuclei could influence in vitro transcription (Manzoli et al., 1978). The same group demonstrated that negatively charged lipids led to chromatin decondensation, while positive charged lipids had the opposite effect. In 1987, the first demonstration came from a work by Cocco et al., that a nuclear PI metabolism exists and it is regulated during Friend cells differentiation (Cocco et al., 1987). Since then, progress has been made on the regulation of nuclear phosphoinositides (PI), as well as their role in cellular functions, i.e. growth and differentiation. Nevertheless, much still needs to be understood about the function, regulation and physical properties of this nuclear component. For example, while it is clear that these PIs are not part of the nuclear envelope but they reside within the nuclear domains, the physicochemical form of nuclear lipids still needs to be clarified (Irvine, 2006). We know that inositol lipid signaling molecules are essential components of the extremely complicated, multistep process that allows one extracellular signal to be transduced inside the cell, to the nucleus. In the nuclear compartment, lipid second messengers elicit reactions that regulate gene transcription, DNA replication or repair, and DNA cleavage, eventually resulting in cellular differentiation, proliferation, apoptosis and other cell functions. Inositol-containing phospholipids are the most intensively studied lipid second messengers. Albeit most of the research on signal transduction pathways based on PI has been devoted to phenomena that take place at the cell periphery and plasma membrane, it has become clear that the nuclear PI cycle is regulated in a totally independent manner from that at the plasma membrane level. This suggests that nuclear inositol lipids themselves can modulate nuclear processes, as important as transcription and pre-mRNA splicing, growth, proliferation, cell cycle regulation and differentiation.