Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes

Xian, Jie; Obeng, Eric Owusu; Ratti, Stefano; Rusciano, Isabella; Marvi, Maria Vittoria; Fazio, Alessia; Stefano, Alessia De; Mongiorgi, Sara; Cappellini, Alessandra; Ramazzotti, Giulia; Cocco, Lucio; Follo, Matilde Y.

doi:10.3390/cells9030697

Cited by 11 publications

(10 citation statements)

References 123 publications

(134 reference statements)

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“…In hematopoiesis, and particularly in MDS, PLCβ1 is associated with both myelopoiesis and erythropoiesis, although with opposite effects [ 54 , 55 , 56 ].…”

Section: Targeting Inositide-dependent Signal Transduction Pathwaymentioning

confidence: 99%

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi

Finelli

Fazio

et al. 2021

IJMS

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Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.

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“…In hematopoiesis, and particularly in MDS, PLCβ1 is associated with both myelopoiesis and erythropoiesis, although with opposite effects [ 54 , 55 , 56 ].…”

Section: Targeting Inositide-dependent Signal Transduction Pathwaymentioning

confidence: 99%

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Parisi

Finelli

Fazio

et al. 2021

IJMS

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“…Furthermore, RhoA [55] and the RAS family of small GTPases, (RAS, RAS-related protein (Rap1) and Rap2B) [29,56] are able to activate PLCε through direct binding to the various domains of PLCε (Figure 2c). PLCε localizes within different cellular sub-compartments following its binding to Rap1 and RAS [29] or different cellular stimulations [37]: in perinuclear space [29,57], cytoplasm, and plasma membrane [29]. The ability of PLCε to be activated via several stimuli and its distribution across several cellular sub-compartments makes it one of the most complex signaling hubs.…”

Section: Plcδmentioning

confidence: 99%

“…CAL-101 or idelalisib which is an approved PI3K inhibitor induces elevated cell death in chronic lymphocytic leukemia [82]. Interestingly, alterations in both PLCβ1 and PI3K/Akt/mTOR pathways have been associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [57,83,84]. MDS are a group of hematological diseases characterized by impairment in cell differentiation and proliferation [79,85].…”

Section: Plcs In Cancer Cell Proliferation Survival and Tumor Growthmentioning

confidence: 99%

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

Obeng

Rusciano

Marvi

et al. 2020

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Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP3) by hydrolyzing PtdIns(4,5)P2. DAG and InsP3 regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca2+) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types.

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“…Moreover, DGKs θ and ζ are found at the plasma membrane upon activation of some G protein-coupled receptors (Table 1) [73,74]. Several studies showed that the nuclear inositide signaling is involved in regulating essential cellular processes, such as cell cycle and differentiation [75][76][77][78], while it is also implicated in several pathologies, including myelodysplastic syndromes, brain diseases, and cancer [79][80][81][82]. Interestingly, DGKs, which have been discovered in nearly all cell compartments, were also found in the nucleus.…”

Section: Cellular Localization and Distribution Of Dgksmentioning

confidence: 99%

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases

Fazio

Obeng

Rusciano

et al. 2020

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An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA.

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Nuclear Inositides and Inositide-Dependent Signaling Pathways in Myelodysplastic Syndromes

Cited by 11 publications

References 123 publications

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

Clinical and Molecular Insights in Erythropoiesis Regulation of Signal Transduction Pathways in Myelodysplastic Syndromes and β-Thalassemia

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

Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases

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