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Extracellular superoxide dismutase regulates the expression of small gtpase regulatory proteins GEFs, GAPs, and GDI.

Significance Statement 

Extracellular superoxide dismutase (SOD3) is a redox enzyme that removes superoxide radical (O2-) and produces hydrogen peroxide (H2O2). Previous reports have shown that superoxide dismutase SOD3 either inhibits or promotes growth depending on the study set up and the models used. According to our recent work superoxide dismutase SOD3 regulates the cell growth in a dose-dependent manner: a robust over-expression inhibits growth while moderately upregulated expression stimulates growth signaling and cell proliferation. In the current work published in PLOS One we demonstrated that superoxide dismutase SOD3 activates the mitogen signaling influencing the expression of guanine nucleotide exchange factors (GEF), GTPase activating proteins (GAP), and guanine nucleotide dissociation inhibitors (GDI) that are responsible of RAS and other small GTPase activation. We further published data showing the effect of SOD3 over-expression on the activation of tyrosine kinase receptors, the activation of non-receptor tyrosine kinases, and on the expression of growth related genes by protoarrays, Western blotting and microarray. Thus, the paper published in PLOS One gives guidelines how SOD3 over-expression affects the growth -related cellular signal transduction pathways and transcriptome. The paper may further identify druggable targets of SOD3 -mediated signaling events.

Figure legend

Impact of SOD3 on growth signaling. superoxide dismutase SOD3 affects the signal transduction through small GTPases by regulating the expression of small GTPase regulatory genes GEF, GAP, and GDI in a dose-dependent manner. A moderate over-expression of SOD3 upregulates GEFs and downregulates GAPs and GDI, thus maintaining active RAS. The high over-expression of superoxide dismutase SOD3 downregulates GEFs and upregulates GAPs and GDIs causing the inactivation of RAS.

Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI

 

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Laukkanen MO1, Cammarota F1, Esposito T1, Salvatore M2, Castellone MD3. PLoS One. 2015 ;10(3):e0121441.

Show Affiliations

1IRCCS SDN, Naples, Italy.

2Department of Biomorphological and Functional Sciences, University of Naples Federico II, Naples, Italy.

3Institute of Experimental Endocrinology and Oncology (IEOS/CNR), Naples, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

Abstract

Extracellular superoxide dismutase (SOD3), which catalyzes the dismutation of superoxide anions to hydrogen peroxide at the cell membranes,regulates the cellular growth in a dose-dependent manner. This enzyme induces primary cell proliferation and immortalization at low expressionlevels whereas it activates cancer barrier signaling through the p53-p21 pathway at high expression levels, causing growth arrest, senescence, and apoptosis. Because previous reports suggested that the SOD3-induced reduction in the rates of cellular growth and migration also occurred in the absence of functional p53 signaling, in the current study we investigated the SOD3-induced growth-suppressive mechanisms in anaplastic thyroid cancer cells. Based on our data, the robust over-expression of SOD3 increased the level of phosphorylation of the EGFR, ERBB2, RYK, ALK, FLT3, and EPHA10 receptor tyrosine kinases with the consequent downstream activation of the SRC, FYN, YES, HCK, and LYN kinases. However, pull-down experiments focusing on the small GTPase RAS, RAC, CDC42, and RHO revealed a reduced level of growth and migration signal transduction, such as the lack of stimulation of the mitogen pathway, in the SOD3 over-expressing cells, which was confirmed by MEK1/2 and ERK1/2 Western blotting analysis. Interestingly, the mRNA expression analyses indicated that SOD3 regulated the expression of guanine nucleotide-exchange factors (RHO GEF16, RAL GEF RGL1), GTPase-activating proteins (ARFGAP ADAP2, RAS GAP RASAL1, RGS4), and a Rho guanine nucleotide-disassociation inhibitor (RHO GDI 2) in a dose dependent manner, thus controlling signaling through the small G protein GTPases. Therefore, our current data may suggest the occurrence of dose-dependent SOD3-driven control of the GTP loading of small G proteins indicating a novel growthregulatory mechanism of this enzyme.

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