Nuclear inositides: PI-PLC signaling in cell growth, differentiation and pathology

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Introduction

The existence of phospholipids in chromosomes has been suggested by the work of La Cour et al. (1958). In the 1970s, Manzoli and colleagues demonstrated that addition of phospholipids to purified nuclei could influence in vitro transcription (Manzoli et al., 1978). The same group demonstrated that negatively charged lipids led to chromatin decondensation, while positive charged lipids had the opposite effect. In 1987, the first demonstration came from a work by Cocco et al., that a nuclear PI metabolism exists and it is regulated during Friend cells differentiation (Cocco et al., 1987). Since then, progress has been made on the regulation of nuclear phosphoinositides (PI), as well as their role in cellular functions, i.e. growth and differentiation. Nevertheless, much still needs to be understood about the function, regulation and physical properties of this nuclear component. For example, while it is clear that these PIs are not part of the nuclear envelope but they reside within the nuclear domains, the physicochemical form of nuclear lipids still needs to be clarified (Irvine, 2006).

We know that inositol lipid signaling molecules are essential components of the extremely complicated, multistep process that allows one extracellular signal to be transduced inside the cell, to the nucleus. In the nuclear compartment, lipid second messengers elicit reactions that regulate gene transcription, DNA replication or repair, and DNA cleavage, eventually resulting in cellular differentiation, proliferation, apoptosis and other cell functions. Inositol-containing phospholipids are the most intensively studied lipid second messengers. Albeit most of the research on signal transduction pathways based on PI has been devoted to phenomena that take place at the cell periphery and plasma membrane, it has become clear that the nuclear PI cycle is regulated in a totally independent manner from that at the plasma membrane level. This suggests that nuclear inositol lipids themselves can modulate nuclear processes, as important as transcription and pre-mRNA splicing, growth, proliferation, cell cycle regulation and differentiation.

Phosphatidylinositol(4,5)bisphosphate (PIP2) is a key lipid molecule in the PI cycle. It is the substrate of enzymes involved in signal transduction, such as phosphatidylinositol-specific phospholipase C (PI-PLC) and phosphoinositide 3′-OH kinase (PI3K), thus producing the second messengers diacylglycerol (DAG), inositol trisphosphate (IP3) and phosphatidylinositol(3,4,5)trisphosphate (PIP3). PIP2 has also been shown to be directly involved in chromatin remodeling, by binding to proteins such as histone H1 and the Brahma-related gene associated factor (BAF) complex (Yu et al., 1998, Zhao et al., 1998). This double function of PIP2 in the nucleus, both as substrate for second messenger generation and as chromatin remodeling element, adds further emphasis to the importance of the enzymes responsible for nuclear PIP2 metabolism.

In this review we shall focus on the nuclear PI-PLC, and only briefly consider nuclear PI3K and PIP kinases. In particular, we shall review the most update literature on PI-PLC β1, but it should be kept in mind that also PI-PLC γ1 and PI-PLC δ1 isoforms are present in the nucleus and function in a cell cycle-dependent manner. In particular, PI-PLC γ1 is activated in the cytosol by receptor tyrosine kinases and translocates to the nucleus, where it acts as a guanine nucleotide exchange factor (GEF) for the nuclear GTPase PI3K enhancer (PIKE), which subsequently activates PI3K.

Section snippets

Subnuclear location of PI-PLC β1

Four PI-PLC β isotypes and additional splice variants have been identified in mammals (for a comprehensive state of the art see ref. Rebecchi and Pentyala, 2000). These isoforms are regulated by heterotrimeric GTP-binding proteins, and have a high GTPase stimulating (GAP) activity. Mammalian PI-PLC β isozymes are differentially distributed in tissues, with the PI-PLC β1 being most widely expressed, especially in specific regions of the brain. PI-PLC β1 exists as alternatively spliced variants

Nuclear PI-PLC β1 and mitogenesis

Our laboratory showed that the role of PI-PLC β1 is essential in the IGF-1 mitogenic signaling pathway, because down-regulation of this enzyme by antisense RNA causes an insensitivity of Swiss 3T3 cells to IGF-1, but not, for example, to platelet-derived growth factor (Manzoli et al., 1997). This was confirmed by a separate study, where the IGF-1-dependent nuclear PI-PLC β1 activity increase was blocked by a selective pharmacological inhibitor. In this case, there was no increase in nuclear DAG

PI-PLC β1 during Friend erythroleukemia cells differentiation

Our laboratory showed that nuclear PI metabolism changes during dimethyl sulfoxide (DMSO)-induced erythroid differentiation of the Friend erytholeukemia cell line (MEL) (Cocco et al., 1987). Subsequently, we demonstrated that the DMSO-induced differentiation of these cells is accompanied by a progressive decrease of replicative activity and accumulation of nuclear PIP2 (Manzoli et al., 1989). The increased in vitro synthesis of PIP2 in nuclei of differentiating MEL cells led to the novel idea

PI-PLC β1 during C2C12 myoblast differentiation

The C2C12 myogenic cell line has been widely used to study muscle cell differentiation and the involvement of PI-PLC β1 in this process. Muscle development is characterized by a few well defined steps. The first step involves the determination of which cell will give rise to the myoblast, then the proliferating myoblasts withdraw from the cell cycle, to align and fuse to form multinucleate myotubes. Before the onset of muscle differentiation, proliferating myoblasts express the two myogenic

PLC-β1 and hematological malignancies

The involvement of PI-PLC β1 in hematopoietic differentiation, i.e. affecting CD24 expression (Fiume et al., 2005), prompted us to investigate the role of this signaling molecule in hematological malignancies, focusing particularly on patients affected by myelodysplastic syndromes (MDS) at higher risk of evolution into acute myeloid leukemia (AML). By using fluorescence in situ hybridization (FISH) analysis, our group demonstrated, in a small number of high-risk MDS patients (Lo Vasco et al.,

PI-PLC β1 isozyme expression and DNA methyltransferase inhibition

It has been shown that a DNA methyltransferase inhibitor currently approved for the treatment of MDS and under experimental evaluation for other hematological malignancies, i.e. azacytidine, also affects PI-PLC β1 expression (Kaminskas et al., 2005). Besides showing response rates of 50–80% in MDS, azacytidine has been reported to have a significant impact on the quality of life and progression into AML (Silverman et al., 2002). Nevertheless, the molecular mechanisms underlying this drug are

Summary

The existence of an inositide-dependent nuclear signaling has been clearly shown. In this review we focused on the nuclear PI-PLC signaling activity and its downstream effects. The main isoform present in the nucleus is PI-PLC β1 and this isoform resides in the nuclear domains called speckles and colocalizes with the splicing factor SC35. PI-PLC β1 is also involved in the physiological control of the cell cycle. Moreover, acting on the cyclin D3 promoter plays a crucial role in the process of

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References (71)

  • R. Fiume et al.

    Nuclear phospholipase C beta1 (PLCbeta1) affects CD24 expression in murine erythroleukemia cells

    J Biol Chem

    (2005)
  • J.R. Gruber et al.

    Retinoic acid specifically increases nuclear PKC alpha and stimulates AP-1 transcriptional activity in B16 mouse melanoma cells

    Exp Cell Res

    (1995)
  • R.F. Irvine

    Nuclear inositide signalling – expansion, structures and clarification

    Biochim Biophys Acta

    (2006)
  • C.G. Kim et al.

    The role of carboxyl-terminal basic amino acids in Gqalpha-dependent activation, particulate association, and nuclear localization of phospholipase C-beta1

    J Biol Chem

    (1996)
  • A. Lassar et al.

    Wiring diagrams: regulatory circuits and the control of skeletal myogenesis

    Curr Opin Cell Biol

    (1994)
  • A.P. Los et al.

    The retinoblastoma family proteins bind to and activate diacylglycerol kinase zeta

    J Biol Chem

    (2006)
  • F.A. Manzoli et al.

    Nuclear polyphosphoinositides during cell growth and differentiation

    Adv Enzyme Regul

    (1989)
  • L.M. Neri et al.

    Nuclear diacylglycerol produced by phosphoinositide-specific phospholipase C is responsible for nuclear translocation of protein kinase C-alpha

    J Biol Chem

    (1998)
  • B. Payrastre et al.

    A differential location of phosphoinositide kinases, diacylglycerol kinase, and phospholipase C in the nuclear matrix

    J Biol Chem

    (1992)
  • A. Pombo et al.

    The localization of sites containing nascent RNA and splicing factors

    Exp Cell Res

    (1996)
  • G. Ramazzotti et al.

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

    Cell Signal

    (2008 Nov)
  • E.M. Ross et al.

    Structural determinants for phosphatidic acid regulation of phospholipase C-beta1

    J Biol Chem

    (2006)
  • J.W. Soh et al.

    Roles of specific isoforms of protein kinase C in the transcriptional control of cyclin D1 and related genes

    J Biol Chem

    (2003)
  • G. Tabellini et al.

    Diacylglycerol kinase-theta is localized in the speckle domains of the nucleus

    Exp Cell Res

    (2003)
  • Z. Wang et al.

    Characterization of the mouse cyclin D3 gene: exon/intron organization and promoter activity

    Genomics

    (1996)
  • K. Zhao et al.

    Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling

    Cell

    (1998)
  • A. Bavelloni et al.

    Proteomic-based analysis of nuclear signaling: PLCbeta1 affects the expression of the splicing factor SRp20 in Friend erythroleukemia cells

    Proteomics

    (2006)
  • I.V. Boronenkov et al.

    Phosphoinositide signaling pathways in nuclei are associated with nuclear speckles containing pre-mRNA processing factors

    Mol Biol Cell

    (1998)
  • J.F. Caceres et al.

    Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity

    J Cell Biol

    (1997)
  • J.F. Caceres et al.

    A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm

    Genes Dev

    (1998)
  • C. Cenciarelli et al.

    Critical role played by cyclin D3 in the MyoD-mediated arrest of cell cycle during myoblast differentiation

    Mol Cell Biol

    (1999)
  • L. Cocco et al.

    Synthesis of polyphosphoinositides in nuclei of Friend cells. Evidence for polyphosphoinositide metabolism inside the nucleus which changes with cell differentiation

    Biochem J

    (1987)
  • N. Divecha et al.

    The polyphosphoinositide cycle exists in the nuclei of Swiss 3T3 cells under the control of a receptor (for IGF-I) in the plasma membrane, and stimulation of the cycle increases nuclear diacylglycerol and apparently induces translocation of protein kinase C to the nucleus

    Embo J

    (1991)
  • N. Divecha et al.

    Changes in the components of a nuclear inositide cycle during differentiation in murine erythroleukaemia cells

    Biochem J

    (1995)
  • C. Evangelisti et al.

    Subnuclear localization and differentiation-dependent increased expression of DGK-zeta in C2C12 mouse myoblasts

    J Cell Physiol

    (2006)
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