The physiology and pathology of inositide signaling in the nucleus

Ramazzotti, Giulia; Faenza, Irene; Fiume, Roberta; Matteucci, Alessandro; Piazzi, Manuela; Follo, Matilde Y.; Cocco, Lucio

doi:10.1002/jcp.22334

Cited by 34 publications

(29 citation statements)

References 79 publications

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“…Within the hematological fi eld, not only PI-PLC ␤ 3, but also other PI-PLC ␤ isozymes have been demonstrated to play a role in the pathophysiology of hematologic diseases (76)(77)(78)(79). Indeed, the PI-PLC ␤ 1 gene has been associated with myelodysplastic syndrome (MDS), not only because its lack is linked to MDS progression toward acute myeloid leukemia ( 80,81 ), but also because its expression is regulated by epigenetic mechanisms (82)(83)(84)(85).…”

Section: Splicing Variants Of Pi-plcmentioning

confidence: 99%

Phosphoinositide-specific phospholipase C in health and disease

Cocco

Follo

Manzoli

et al. 2015

Journal of Lipid Research

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Section: Splicing Variants Of Pi-plcmentioning

confidence: 99%

Phosphoinositide-specific phospholipase C in health and disease

Cocco

Follo

Manzoli

et al. 2015

Journal of Lipid Research

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140

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“…For instance, epigenetic regulation of phosphoinositide-phospholipase C (PI-PLC) b 1 promoter, which affects key molecules involved in cell cycle and differentiation (8,9) such as cyclin D3, seems to play an important role in the demethylating activity of azacytidine (10)(11)(12). Indeed, PI-PLCb1 is a central molecule in normal cell proliferation and differentiation (13,14), as well as in hematologic malignancies, such as MDS (15,16). In fact, MDS showing a PI-PLCb1 monoallelic deletion are associated with a higher risk of AML evolution (17), and PI-PLCb1 deregulation affects both myeloid and erythroid differentiation of low-risk MDS cells (18,19).…”

Section: Introductionmentioning

confidence: 99%

Prospective Phase II Study on 5-Days Azacitidine for Treatment of Symptomatic and/or Erythropoietin Unresponsive Patients with Low/INT-1–Risk Myelodysplastic Syndromes

Filì

Malagola

Follo

et al. 2013

Clinical Cancer Research

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Purpose: This phase II prospective study aimed to evaluate the efficacy and safety of 5-days azacytidine (5d-AZA) in patients with low-risk myelodysplastic syndromes (MDS). Second, single-nucleotide polymorphism (SNP) genetic profile and phosphoinositide-phospholipase C (PI-PLC) b1 levels were studied to evaluate possible biologic markers able to predict the hematologic response.Experimental Design: The study tested a lower intensity schedule of azacytidine. The treatment plan consisted of 75 mg/sqm/d subcutaneous administered for 5 days every 28 days, for a total of 8 cycles.Results: Thirty-two patients were enrolled in the study. The overall response rate was 47% (15 of 32) on intention-to-treat and 58% (15 of 26) for patients completing the treatment program. In this latter group, 5 (19%) achieved complete remission (CR) and 10 (38%) had hematologic improvement, according to the International Working Group (IWG) criteria. Three patients have maintained their hematologic improvement after 37, 34, and 33 months without other treatments. Moreover, 21 and 2 of 26 cases completing 8 cycles were transfusion-dependent for red blood cells and platelets at baseline, respectively. Of these, 7 (33%) and 2 (100%) became transfusion-independent at the end of the treatment program, respectively. Grade 3-4 neutropenia occurred in 28% of patients and 4 patients died early due to infections or hemorrhage. SNP results were not significantly correlated to the clinical outcome, whereas PI-PLCb1 level anticipated either positive or negative clinical responses.Conclusions: 5d-AZA is safe and effective in a proportion of patients with low-risk MDS. PI-PLCb1 gene expression is a reliable and dynamic marker of response that can be useful to optimize azacytidine therapy.

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“…Phosphoinositide signaling has been implicated in several cellular functions, and one of the key regulators of this pathway is phosphoinositidespecific phospholipase C β1 (PI-PLCβ1), an enzyme that catalyzes the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), important second messengers that control numerous cellular functions (6)(7)(8)(9)(10). There are two alternative splicing variants of PI-PLCβ1, PI-PLCβ1a and PI-PLCβ1b (9), each of which has a different cellular localization (1a, both cytoplasmic and nuclear; 1b, predominantly nuclear) and modes of activation (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

PI-PLCβ1 gene copy number alterations in breast cancer

et al. 2011

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Abstract. Deregulation of signal transduction pathways frequently confers selective biological advantages to tumors. Phosphoinositides play an essential role in numerous cellular functions and, among the enzymes implicated in these processes, phosphoinositide-specific phospholipase C β1 (PI-PLCβ1) is one of the key regulators. In the present study, a fluorescence in situ hybridization (FISH) approach was used to investigate PI-PLCβ1 gene copy number alterations in various types of breast cancer differing in their invasiveness and proliferative activity, according to their mitotic index. At the molecular level, we also performed both real-time PCR and immunohistochemical analyses on PI-PLCβ1 to further investigate its expression in primary breast cancers. Finally, we analyzed the correlation between PI-PLCβ1 gene copy number and clinicopathological parameters. Our results show that most of our cases had aneusomies on the PI-PLCβ1 locus (20p12) and amplification of this specific region was the most frequent alteration observed. Our findings also indicate that the amplification of the region containing the PI-PLCβ1 gene was mostly related to the mitotic index, rather than to the invasion status. Finally, even though our case series is limited, PI-PLCβ1 gene amplification seems to be correlated to clinicopathological parameters.

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The physiology and pathology of inositide signaling in the nucleus

Cited by 34 publications

References 79 publications

Phosphoinositide-specific phospholipase C in health and disease

Phosphoinositide-specific phospholipase C in health and disease

Prospective Phase II Study on 5-Days Azacitidine for Treatment of Symptomatic and/or Erythropoietin Unresponsive Patients with Low/INT-1–Risk Myelodysplastic Syndromes

PI-PLCβ1 gene copy number alterations in breast cancer

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