Nuclear Inositide Signaling Via Phospholipase C

Abstract

The existence of an independent nuclear inositide pathway distinct from the cytoplasmic one has been demonstrated in different physiological systems and in diseases. In this prospect we analyze the role of PI-PLCβ1 nuclear isoform in relation to the cell cycle regulation, the cell differentiation, and different physiopathological pathways focusing on the importance of the nuclear localization from both molecular and clinical point of view. PI-PLCβ1 is essential for G1/S transition through DAG and Cyclin D3 and plays also a central role in G2/M progression through Cyclin B1 and PKCα. In the differentiation process of C2C12 cells PI-PLCβ1 increases in both myogenic differentiation and osteogenic differentiation. PI-PLCβ1 and Cyclin D3 reduction has been observed in Myotonic Dystrophy (DM) suggesting a pivotal role of these enzymes in DM physiopathology. PI-PLCβ1 is also involved in adipogenesis through a double phase mechanism. Moreover, PI-PLCβ1 plays a key role in the normal hematopoietic differentiation where it seems to decrease in erythroid differentiation and increase in myeloid differentiation. In Myelodysplastic Syndromes (MDS) PI-PLCβ1 has a genetic and epigenetic relevance and it is related to MDS patients' risk of Acute Myeloid Leukemia (AML) evolution. In MDS patients PI-PLCβ1 seems to be also a therapeutic predictive outcome marker. In the central nervous system, PI-PLCβ1 seems to be involved in different pathways in both brain cortex development and synaptic plasticity related to different diseases. Another PI-PLC isozyme that could be related to nuclear activities is PI-PLCζ that is involved in infertility processes. J. Cell. Biochem. 118: 1969-1978, 2017. © 2017 Wiley Periodicals, Inc.

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

“…PLCs comprise of 6 sub-family members which hydrolyze PtdIns(4,5)P 2 to generate the two essential intracellular second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP 3 ) following their activation. This promotes the activation of protein kinase C (PKC) and the release of calcium ions (Ca 2+ ) from the intracellular stores, respectively [21][22][23][24]. InsP 3 detaches from the membrane and interacts with InsP 3 -specific receptors to regulate Ca 2+ release, while DAG remains membrane-bound to mediate the activation of PKC upon Ca 2+ release [25].…”

“…PLCs are distributed across several cellular compartments depending on the localization of their substrate PIs. For instance, PIs have been shown to localize within the nucleus together with their metabolic enzymes which help to generate a separate PI metabolism that is distinct from the cytoplasmic PI cycle [21,31]. Some PLC isoforms like PLCβ1 [32,33], PLCγ1 [34], PLCδ1 [35], PLCδ4 [36], and PLCε [37] have been reported to localize in the nucleus.…”

Nuclear translocation of PKC‐ α is associated with cell cycle arrest and erythroid differentiation in myelodysplastic syndromes (MDSs)

“…Notably, the above‐mentioned decrease in PKC‐α has been found in total lysates of the human K562 erythroleukemia cell line, but the behavior of PKC‐α could change in nuclear and cytoplasmic fractions. Indeed, the cellular localization of the PI metabolism is extremely important because its enzymes may have different regulations and functions according to their localization (29–32).…”

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases

“…Accumulating evidence demonstrates that DGKs, as well as phospholipases C (PLCs) and PKCs, are distributed across several subcellular compartments together with their substrates [ 15 , 16 , 17 ] and, as PLCs and PKCs, they are involved in cell regulation [ 18 , 19 ]. Nuclear localization allows DGKs to participate in a PI cycle which is independent of that of the plasma membrane [ 20 , 21 ].…”