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SOD3 Is a Non-Mutagenic Growth Regulator Affecting Cell Migration and Proliferation Signal Transduction.

ABSTRACT: Superoxide dismutase (SOD) family isoenzymes, SOD1, SOD2, and SOD3, synthesize hydrogen peroxide (H₂O₂), which regulates the signal transduction. H₂O₂ is a second messenger able to enter into the cells through aquaporin 3 cell membrane channels and to modify protein tyrosine phosphatase activity. SOD3 has been shown to activate signaling pathways in tissue injuries, inflammation, and cancer models. Similar to the H₂O₂ response in the cells, the cellular response of SOD3 is dose-dependent; even a short supraphysiological concentration reduces the cell survival and activates the growth arrest and apoptotic signaling, whereas the physiological SOD3 levels support its growth and survival. In the current work, we studied the signaling networks stimulated by SOD3 overexpression demonstrating a high diversity in the activation of signaling cascades. The results obtained suggest that SOD3, although inducing cell growth and affecting various biological processes, does not cause detectable long-term DNA aberrations. Therefore, according to the present data, SOD3 is not a mutagen. Additionally, we compared SOD3-driven immortalized mouse embryonic fibroblasts to SV40 immortalized NIH3T3 cells, demonstrating a marked difference in the activation of cellular kinases. The data presented may contain important druggable targets to abrogate unwanted cell growth.

SUBMITTER: Parascandolo A

PROVIDER: S-EPMC8143115 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledBacteriophytochrome photoreceptors (BphPs) and their cognate response regulators make up two-component signal transduction systems which direct bacteria to mount phenotypic responses to changes in environmental light quality. Most of these systems utilize single-domain response regulators to transduce signals through unknown pathways and mechanisms. Here we describe the photocycle and autophosphorylation kinetics of RtBphP1, a red light-regulated histidine kinase from the desert bacterium Ramlibacter tataouinensis RtBphP1 undergoes red to far-red photoconversion with rapid thermal reversion to the dark state. RtBphP1 is autophosphorylated in the dark; this activity is inhibited under red light. The RtBphP1 cognate response regulator, the R. tataouinensis bacteriophytochrome response regulator (RtBRR), and a homolog, AtBRR from Agrobacterium tumefaciens, crystallize unexpectedly as arm-in-arm dimers, reliant on a conserved hydrophobic motif, hFWAhL (where h is a hydrophobic M, V, L, or I residue). RtBRR and AtBRR dimerize distinctly from four structurally characterized phytochrome response regulators found in photosynthetic organisms and from all other receiver domain homodimers in the Protein Data Bank. A unique cacodylate-zinc-histidine tag metal organic framework yielded single-wavelength anomalous diffraction phases and may be of general interest. Examination of the effect of the BRR stoichiometry on signal transduction showed that phosphorylated RtBRR is accumulated more efficiently than the engineered monomeric RtBRR (RtBRRmon) in phosphotransfer reactions. Thus, we conclude that arm-in-arm dimers are a relevant signaling intermediate in this class of two-component regulatory systems.ImportanceBphP histidine kinases and their cognate response regulators comprise widespread red light-sensing two-component systems. Much work on BphPs has focused on structural understanding of light sensing and on enhancing the natural infrared fluorescence of these proteins, rather than on signal transduction or the resultant phenotypes. To begin to address this knowledge gap, we solved the crystal structures of two single-domain response regulators encoded by a region immediately downstream of that encoding BphPs. We observed a previously unknown arm-in-arm dimer linkage. Monomerization via deletion of the C-terminal dimerization motif had an inhibitory effect on net response regulator phosphorylation, underlining the importance of these unusual dimers for signal transduction.

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SOD3 Is a Non-Mutagenic Growth Regulator Affecting Cell Migration and Proliferation Signal Transduction.

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