Towards the Deciphering of the Nuclear Inositol Lipid Signal Transduction Code

Once established that the nuclear inositol lipid signal transduction presents some of the crucial characteristics of an organic code, the further step should imply the deciphering of the code by which the system works. We know for sure that the understanding of other organic codes, such as splicing code and histone code, is still extraordinarily difficult; nevertheless we have some indications that the bases for understanding the inositol lipid signal transduction code have been posed.

Phosphoinositides are known to transduce signals essentially via two events: their modification and their interaction with specific proteins. In the nucleus it has been demonstrated that some phosphoinositide species are specifically represented, and nuclear proteins have been identified capable of interacting with these phosph-oinositides. The main nuclear phosphoinositides are represented by PIPs, PI(4,5)P2 and inositol phosphates, whose relative amounts vary in response to environmental conditions. Protein domains that interact with phosphoinositides include PH, ENTH, FYVE, PHOX domains, PHD finger and lysine/arginine rich patches. Many of the cellular proteins that display these domains are nuclear, being chromatin-associated or lamina-associated proteins, capable of modulating chromatin remodelling and gene domain positioning. It has been largely demonstrated that extracellular signals that induce processes such as cell proliferation, differentiation, and stress adaptation/apoptosis, lead to temporal and spatial changing in nuclear inositide profiles. This results in specific relative proportions of the different nuclear inositide pool. The combinatorial changes in nuclear phosphoinositides could be decoded through their interaction with specific phosphoinositide-binding proteins to elicit differential outputs (Fig. 4).

These may include changes in chromatin structure to regulate gene expression, DNA replication or repair. For example, signal inputs that increase the level of nuclear PI(5)P within the chromatin lead to the translocation of ING2 that, in turn, may regulate p53 function and histone acetylation to coordinate the apoptotic response (Jones and Divecha, 2004). Moreover, intranuclear changes of the PI(4,5)P2 pool have been demonstrated to modulate chromatin remodelling complex activity (Rando et al., 2002) which are essential to induce gene transcription. These experimental findings strongly suggest that the transductional complexes constituted by phosphoinosites-proteins, located at different nuclear domains behave as adaptors, suggesting a key towards the deciphering of the nuclear inositide signal transduction code.

Fig. 4 In the drawing the size of the oval reflects the relative amount of the nuclear inositide pool. The interaction of the more represented nuclear inositide with chromatin-associated proteins (shaded) leads, in response to extracellular signals, to differential processes, such as cell differentiation, proliferation, or apoptosis

Fig. 4 In the drawing the size of the oval reflects the relative amount of the nuclear inositide pool. The interaction of the more represented nuclear inositide with chromatin-associated proteins (shaded) leads, in response to extracellular signals, to differential processes, such as cell differentiation, proliferation, or apoptosis

Was this article helpful?

0 0

Post a comment