PLC-β1 and cell differentiation: An insight into myogenesis and osteogenesis

Ramazzotti, Giulia; Faenza, Irene; Fiume, Roberta; Billi, Anna Maria; Manzoli, Lucia; Mongiorgi, Sara; Ratti, Stefano; McCubrey, James A.; Suh, Pann Ghill; Cocco, Lucio; Follo, Marie

doi:10.1016/j.jbior.2016.10.005

Cited by 37 publications

(31 citation statements)

References 43 publications

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“…In fact, full activation of the Wnt pathway seems to require Ins(1,3,4,5,6)P 5 , because upon Wnt stimulation, IPMK is recruited to the plasma membrane via its interaction with Dishevelled-3 (Wang and Wang, 2012). Another recent report defining the role IPMK plays in promoting phospholipase Cβ1-dependent myogenic differentiation in C2C12 cells further corroborates the physiological significance of IPMK’s catalytic activity in controlling β-catenin activation (Ramazzotti et al, 2016; 2017). …”

Section: Ipmk-dependent Inositol Polyphosphates As Cell Signalssupporting

confidence: 54%

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

Kim¹,

Ahn²,

Kim³

et al. 2017

Molecules and Cells

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The inositol polyphosphates are a group of multifunctional signaling metabolites whose synthesis is catalyzed by a family of inositol kinases that are evolutionarily conserved from yeast to humans. Inositol polyphosphate multikinase (IPMK) was first identified as a subunit of the arginine-responsive transcription complex in budding yeast. In addition to its role in the production of inositol tetrakis- and pentakisphosphates (IP4 and IP5), IPMK also exhibits phosphatidylinositol 3-kinase (PI3-kinase) activity. Through its PI3-kinase activity, IPMK activates Akt/PKB and its downstream signaling pathways. IPMK also regulates several protein targets non-catalytically via protein-protein interactions. These non-catalytic targets include cytosolic signaling factors and transcription factors in the nucleus. In this review, we highlight the many known functions of mammalian IPMK in controlling cellular signaling networks and discuss future challenges related to clarifying the unknown roles IPMK plays in physiology and disease.

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Section: Ipmk-dependent Inositol Polyphosphates As Cell Signalssupporting

confidence: 54%

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

Kim¹,

Ahn²,

Kim³

et al. 2017

Molecules and Cells

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“…These cells are a well-established primary murine myoblast model cell line consistently used for these types of studies [29]. We generated two myoblast cells lines with decreased levels of CSN3 shCSN3-Low and shCSN3-Med.…”

Section: Discussionmentioning

confidence: 99%

“…This study addressed the hypothesis that CSN3 mediates skeletal muscle differentiation in C2C12 cells, which are a well-established primary murine myoblast model cell line consistently used to study skeletal muscle differentiation in vitro [29]. To test this hypothesis, we generated C2C12 stable CSN3 knockdown cell lines via RNAi, and investigated the effects of CSN3 knockdown on CSN complex integrity and C2C12 proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway

Surina

Singer

et al. 2017

BMC Pharmacol Toxicol

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BackgroundThe COP9 signalosome (CSN) is a conserved protein complex composed of 8 subunits designated CSN1-CSN8. CSN3 represents the third subunit of the CSN and maintains the integrity of the complex. CSN3 binds to the striated muscle-specific β1D integrin tail, and its subcellular localization is altered in differentiated skeletal muscle cells. However, the role of CSN3 in skeletal muscle differentiation is unknown. The main goal of this study was to identify whether CSN3 participates in myoblast differentiation and the signalling mechanisms involved using C2C12 cells as a skeletal muscle cell model.MethodsSmall-hairpin (shRNA) was used to knockdown CSN3 in C2C12 cells. Differentiation was evaluated by immunostaining and confocal microscopy. Markers of differentiation, NF-κB signaling and CSN subunits expression, were assessed by immunoblotting and/or immunostaining. Cell proliferation was analysed by cell counting, flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Data were analyzed by one or two-way analysis of variance (ANOVA) followed by post-hoc testing.ResultsTransduction of C2C12 cells with two distinct CSN3 shRNAs led to the production of two cells lines expressing 7% of CSN3 protein (shCSN3-Low) and 43% of CSN3 protein (CSN3-Med) compared to controls. Knockdown of CSN3 was accompanied by destabilization of several CSN subunits and increased nuclear NF-κB localization. shCSN3-Med cells expressed less myogenin and formed shorter and thinner myotubes. In contrast, the shCSN3-Low cells expressed higher levels of myogenin prior and during the differentiation and remained mononucleated throughout the differentiation period. Both CSN3 knockdown cell lines failed to express sarcomeric myosin heavy chain (MHC) protein during differentiation. The fusion index was significantly higher in control cells than in shCSN3-Med cells, whereas shCSN3-Low cells showed no cell fusion. Interestingly, CSN3 knockdown cells exhibited a significantly slower growth rate relative to the control cells. Cell cycle analysis revealed that CSN3 knockdowns delayed in S phase and had increased levels of nuclear p21/Cip1 and p27/Kip1.ConclusionsThis study clarifies the first step toward unrevealing the CSN3/CSN-mediated pathways that controls C2C12 differentiation and proliferation. Further in vivo characterization of CSN/CSN3 may lead to the discovery of novel therapeutic target of skeletal muscle diseases such as muscular dystrophies.

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“…In addition the down‐regulation of PI‐PLCβ1 gene expression results in an inhibition of the osteogenic differentiation process induced in C2C12 by BMP‐2, as demonstrated by Alkaline phosphatase (ALP) reduction. Instead PI‐PLCβ1 overexpression determines an increase of osteogenic differentiation as demonstrated by the rise of ALP and Osx/Sp7 [Ramazzotti et al, ]. Indeed ALP and Bone gamma‐carboxyglutamic acid containing protein (Bglap or Osteocalcin) are osteoblast marker genes that increase in response to the action of the main bone morphogenic proteins that control the osteoblastic differentiation.…”

Section: Nuclear Pi‐plcβ1 In Cell Differentiationmentioning

confidence: 99%

“…There are different pathways related to the myogenic differentiation that can be activated by several events and that can lead to various cellular processes. The two main families of the transcription factors related to myogenic differentiation are the Myogenic Regulatory Factors (MRFs) and the Myocyte Enhancer Facotr‐2 (MEF2) [Ramazzotti et al, ]. C2C12 cells under low serum conditions can differentiate into myotubes.…”

Section: Nuclear Pi‐plcβ1 In Cell Differentiationmentioning

confidence: 99%

Nuclear Inositide Signaling Via Phospholipase C

et al. 2017

Self Cite

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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.

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PLC-β1 and cell differentiation: An insight into myogenesis and osteogenesis

Cited by 37 publications

References 43 publications

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

Knockdown of subunit 3 of the COP9 signalosome inhibits C2C12 myoblast differentiation via NF-KappaB signaling pathway

Nuclear Inositide Signaling Via Phospholipase C

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