Inositide signaling: Nuclear targets and involvement in myelodysplastic syndromes.

Several cellular functions are regulated by inositol lipids. The study of the cell cycle machinery has evidenced an emerging role for nuclear polyphosphoinositides (PIs) (Cocco et al., 2006), which control gene expression both as chromatin structure regulators and as second messengers in a number of signal transduction pathways. Manzoli et al. (1982) demonstrated that nuclear negatively charged lipids bind to chromatin and cause its decondensation. It was later shown that PIs regulate the interaction of BAF (a chromatin remodelling complex) to chromatin and that they counteract H1-mediated repression of basal transcription by RNA polymerase II (Yu et al., 1998). These observations paved the way for recent and intriguing investigations on the mechanisms of PIs regulation of chromatin structure and gene expression. Nuclear inositol lipid metabolism is independently regulated from the plasma membrane PIs cycle, and it constitutes an autonomous signalling system which modulates cell cycle progression and differentiation in response to growth factor stimulation (Irvine, 2003; Manzoli et al., 2005; Martelli et al., 2004). Since the first hints at the existence of a nuclear PIs cycle and its involvement in mitogenic signalling (Cocco et al., 1987), a growing body of evidence is showing that PIs in the nucleus are also involved in cancer cell generation, proliferation and resistance to apoptosis (Martelli et al., 2006a). Most of these observations were made on cell lines, and are being confirmed by the most recent evidence on ex vivo human cancer cells, offering new targets for the development of novel therapeutic strategies for neoplastic diseases, as well as degenerative disorders.