Disease relevance of OXSR1

• Oxidative stress-responsive transcription factor ATF3 potentially mediates diabetic angiopathy [1].

High impact information on OXSR1

• Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity [2].
• BACKGROUND: Rel/NF-kappaB, an oxidative stress-responsive transcription factor, participates transiently in the control of gene expression [3].
• Here we have shown that WNK1 phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) [4].
• WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1 [4].
• OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1 [5].

Chemical compound and disease context of OXSR1

• This study suggests that quercetin and catechin may be of benefit for diabetic vascular complications due to its antioxidant abilities against AGE-mediated oxidative stress through oxidative stress-sensitive and oxidative stress-responsive signaling pathways, which lead to inflammation in human monocytes [6].

Biological context of OXSR1

• The residues on NKCC1, phosphorylated by SPAK/OSR1, are conserved in other cation co-transporters, such as the Na+-Cl- co-transporter, the target of thiazide drugs that lower blood pressure in humans with Gordon's syndrome [7].
• Genetic analysis suggests that OSR1 evolved first, with SPAK arising following a gene duplication in vertebrate evolution [8].
• SPAK and OSR1 are two recently discovered kinases which have been linked to several key cellular processes, including cell differentiation, cell transformation and proliferation, cytoskeleton rearrangement, and most recently, regulation of ion transporters [8].
• Based on the alignment of 12 sequences of protein motifs that interact with the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress response 1), we performed genome-wide searches of the sequence [S/G/V]RFx[V/I]xx[V/I/T/S]xx, where x represents any amino acid [9].
• Taken together, we propose that human Ngb may be a novel oxidative stress-responsive sensor for signal transduction in the brain [10].

Anatomical context of OXSR1

• OSR1 is a 58-kDa protein of 527 amino acids that is widely expressed in mammalian tissues and cell lines [5].
• Characterization of OSR1, a member of the mammalian Ste20p/germinal center kinase subfamily [5].
• By immunocytochemistry, SPAK, OSR1 and phosphorylated focal adhesion kinase (pFAK) were colocalized with NKCC at the basolateral membrane [11].
• A subsequent imbalance in cellular oxidative stress/antioxidant status can activate oxidative stress-responsive transcription factors, which in turn may promote cytokine production, expression of adhesion molecules on the surface of endothelial cells, and thus intensify an inflammatory response in atherosclerosis [12].
• Ngb is held to facilitate O2 diffusion to the mitochondria and to protect neuronal cells from hypoxic-ischemic insults, may be an oxidative stress-responsive sensor protein for signal transduction, and may carry out enzymatic activities, such as NO/O2 scavenging [13].

Associations of OXSR1 with chemical compounds

• Of potential regulators surveyed, endogenous OSR1 is activated only by osmotic stresses, notably sorbitol and to a lesser extent NaCl [5].
• Mutation of Ser325 in OSR1 to alanine or glutamic acid did not affect the basal activity of OSR1 or its ability to be activated by WNK1 [14].
• Mutation of the arginine, phenylalanine or valine residue within this peptide abolishes binding to SPAK/OSR1 [7].
• We conclude that several cation chloride co-transporters interact with SPAK and/or OSR1, and we hypothesize that this interaction might play a role during the initiation of the cellular stress response [15].
• Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress response kinase (OSR1) are two serine/threonine kinases belonging to the germinal centre-like kinase subfamily VI [8].

Regulatory relationships of OXSR1

• We have identified specific residues within the CCT domain that are required for interaction with the RFXV motif and have demonstrated that mutation of these in OSR1 inhibited phosphorylation of NKCC1, but not of CATCHtide which does not possess an RFXV motif [7].

Other interactions of OXSR1

• These data reveal the presence of a novel oxidative stress-responsive 41 kDa Adapt78 species, lend further insight into the Adapt78 family of proteins and their distribution, and challenge previous conclusions obtained using transfection protocols [16].
• Oxidative stress-responsive intracellular regulation specific for the angiostatic form of human tryptophanyl-tRNA synthetase [17].
• An electrophoretic mobility shift assay was used to test the binding affinity of nuclear proteins extracted from the coal-treated HTE cells to an oxidative stress-responsive transcription factor activator protein-1 (AP-1) element [18].
• With such a reliance of cancer cells on H2O2 it follows that if the excess H2O2 can be scavenged by phenolic phytochemicals having antioxidant activity, the oxidative stress-responsive genes can be suppressed and consequently cancer cell proliferation inhibited [19].
• These intermediates can activate oxidative stress-responsive transcription factors, such as NF-kappa B, which in turn may promote cytokine production, adhesion molecule expression and ultimately endothelial barrier dysfunction [20].

Analytical, diagnostic and therapeutic context of OXSR1

• OSR1 was identified through a yeast two-hybrid screen utilizing the intracellular portion of RELL1 as bait, and OSR1 was shown to interact with the three RELT family members by in vitro co-immunoprecipitation experiments [21].
• ZEN mediated induction of oxidative DNA damage (comet assay using the repair enzymes), modulation of gluthatione (GSH), cytotoxicity (growth inhibition) and the oxidative stress responsive gene Hsp 70 and Hsp 90 were investigated with respect to concentration and time dependency [22].

References