Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells.

Diphosphoinositol pentakisphosphate (IP) is critical for the exocytotic capacity of the pancreatic β-cell, but its regulation by the primary instigator of β-cell exocytosis, glucose, is unknown. The high K for ATP of the IP-generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting β-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP concentration in β-cells.

Identification of a functional nuclear export sequence in diacylglycerol kinase-zeta.

Diacylglycerol kinases (DGKs) are key regulators of diacylglycerol-dependent signaling pathways. Among the 10 DGK isoforms, DGK-zeta is the only nuclear form that contains a nuclear localization signal. Here, by site-directed mutagenesis, we showed that DGK-zeta also displays a functional independent nuclear export signal (NES) sequence between the amino acid residues 362-370.

A role for PKCepsilon during C2C12 myogenic differentiation.

In a previous report we have demonstrated that PLCgamma1 is involved in the differentiation process of C2C12 myoblasts, induced by insulin administration. In order to identify the downstream targets of PLCgamma1-dependent signalling, we have analyzed the expression of DAG-dependent PKC isoforms during muscle differentiation. We show that during myotube formation, there is a marked increase of PKCepsilon and eta expression, and that PKCepsilon is able to form a complex with PLCgamma1.

Inositol pyrophosphates: structure, enzymology and function.

The stereochemistry of the inositol backbone provides a platform on which to generate a vast array of distinct molecular motifs that are used to convey information both in signal transduction and many other critical areas of cell biology. Diphosphoinositol phosphates, or inositol pyrophosphates, are the most recently characterized members of the inositide family. They represent a new frontier with both novel targets within the cell and novel modes of action.

TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-zeta-dependent cell cycle arrest.

In addition to lipid second messengers derived from the plasma membrane, increasing evidence supports the existence of nuclear lipid-dependent signaling networks. Diacylglycerol is a key second messenger, generated at the nuclear level, which is metabolized by diacylglycerol kinases (DGKs). It has been demonstrated that nuclear DGK-zeta negatively regulates cell cycle progression.

Catalytic activity of nuclear PLC-beta(1) is required for its signalling function during C2C12 differentiation.

Here we report that PLC-beta(1) catalytic activity plays a role in the increase of cyclin D3 levels and induces the differentiation of C2C12 skeletal muscle cells. PLC-beta(1) mutational analysis revealed the importance of His(331) and His(378) for the catalysis. The expression of PLC-beta(1) and cyclin D3 proteins is highly induced during the process of skeletal myoblast differentiation.

Inositide-dependent phospholipase C signaling mimics insulin in skeletal muscle differentiation by affecting specific regions of the cyclin D3 promoter.

Our main goal in this study was to investigate the role of phospholipase C (PLC) beta(1) and PLCgamma(1) in skeletal muscle differentiation and the existence of potential downstream targets of their signaling activity. To examine whether PLC signaling can modulate the expression of cyclin D3, a target of PLCbeta(1) in erythroleukemia cells, we transfected C2C12 cells with expression vectors containing PLCbeta(1) or PLCgamma(1) cDNA and with small interfering RNAs from regions of the PLCbeta(1) or PLCgamma(1) gene and followed myogenic differentiation in this well-established cell system. Intriguingly, overexpressed PLCbeta(1) and PLCgamma(1) were able to mimic insulin induction of both cyclin D3 and muscle differentiation.

Real-time PCR as a tool for quantitative analysis of PI-PLCbeta1 gene expression in myelodysplastic syndrome.

Phosphoinositide-specific phospholipase C (PI-PLC) beta1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation. In particular, the involvement of the PI-PLCbeta1 gene in erythroid differentiation lead us to investigate this gene in patients affected by high-risk myelodysplastic syndrome (MDS). By using fluorescence in situ hybridization (FISH) analysis, we have previously evidenced that, in MDS patients with normal GTG banding and a fatal outcome, the PI-PLCbeta1 gene undergoes monoallelic and interstitial deletion.

Anticancer agents sensitize osteosarcoma cells to TNF-related apoptosis-inducing ligand downmodulating IAP family proteins.

Although TNF-related apoptosis-inducing ligand (TRAIL) usually induces cell death in tumor cells, there are some tumor cell types that are resistant to its apoptogenic effects. Some chemotherapeutic drugs, however, can sensitize resistant cancer cells to TRAIL by either upregulating surface TRAIL death receptor expression or by modulating intracellular signalling pathways emanating from TRAIL receptors. U2OS human osteosarcoma cells express TRAIL-R2 but are resistant to TRAIL-induced apoptosis.