Nuclear inositide-metabolism in granulocytic differentiation of myeloid cells.

In the last few years, several authors have demonstrated that molecules involved in the inositide pathway, such as inositol lipid kinases and phosphatases, are present in the cell nucleus, and turnover independently of the cytoplasm. Recent works reported the presence of enzymes involved in the inositol lipid signalling in nuclei of the myeloid cell line HL-60, and their involvement in the cellular response of this cells to All trans-retinoic acid (ATRA), an agonist acting through a nuclear receptor with a transcriptional activity. In particolar, specific isoforms of protein kinase C (PKC) and phospholipase C (PLC), as well as phosphoinositide 3-kinase (PI3-K) translocate to the nuclear compartment and are activated during ATRA-induced granulocytic differentiation of this cell line. Of the PKC family, the nuclear ζ isoform seems to be necessary but not sufficient to induce granulocytic differentiation of HL-60. Also PI 3-K appears to be essential for the differentiation process, since the negative modulation of its amount and the specific inhibition of its activity impaired the ATRA-induced modifications of nuclear morphology, typical of neutrophil-like differentiation. The guanosine exchange factor Vav increases its amount and its level of tyrosine-phosphorylation in the nucleus of ATRA-treated cells. An association between tyrosine-phosphorylated Vav, PLC-γl and the p85 regulatory subunit of PI 3-K takes places upon granulocytic differentiation, demonstrating the existence of Vav/ PLC-γl/ PI 3-K complexes in the nucleus of differentiating cells and suggesting for Vav a role in the nuclear trans location of PLC-γl and PI 3-K. The presence in the HL-60 nuclear compartment of molecules known to be involved in the cytoskeletal reorganization, and their nuclear accumulation and activation during ATRA treatment, suggest their cooperative role in regulating the rearrangement of nucleoskeleton typical of granulocytic differentiation.