Disease relevance of PRRX1

• Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology [1].
• NUP98 is fused to PMX1 homeobox gene in human acute myelogenous leukemia with chromosome translocation t(1;11)(q23;p15) [2].
• Chronic granulomatous disease (CGD) can result from any of four single gene defects involving components of the superoxide (O2-.)-generating phagocyte NADPH oxidase (phox) [3].
• Epstein-Barr virus transformed B-lymphocyte cell lines (EBV-B) derived from normal individuals contain phox components and produce O2-., whereas those derived from CGD patients show the CGD defect [3].
• Prx1, a peroxiredoxin family member, was shown to be frequently elevated in lung cancer cells and tissues [4].

High impact information on PRRX1

• The 120-amino acid Phox homology (PX) domain targets proteins to organelle membranes through interactions between two conserved basic motifs within the PX domain and specific PIs [5].
• The human homeodomain protein Phox1 interacts functionally with serum response factor (SRF) to impart serum responsive transcriptional activity to SRF-binding sites in a HeLa cell cotransfection assay [6].
• Furthermore, SPIN binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively with Phox1 to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (SRE) [6].
• While the phox (PX) domain of Snx 17 interacts with phosphatidylinositol-3-phosphate for membrane association, the FERM domain and the carboxyl-terminal region participate in LRP binding [7].
• Further, superoxide production following cholesterol depletion was severely compromised in intact cells or in a cell-free reconstituted system, correlating with a reduced translocation of cytosolic phox subunits to the membrane [8].

Chemical compound and disease context of PRRX1

• Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex [4].

Biological context of PRRX1

• A significant reduction of both steady-state and hypoxia/reoxygenation-mediated prx1 gene expression was shown in Nrf2 knock-out cells [1].
• We hypothesized that the hypoxic and unstable oxygenation microenvironment of a tumor might be crucial for prx1 up-regulation [1].
• The fusion to NUP98 results in the addition of the strong transcriptional activation domain located in the N-terminal region of NUP98 to PMX1 [2].
• Protein and DNA contact surfaces that mediate the selective action of the Phox1 homeodomain at the c-fos serum response element [9].
• To understand the mechanism of action of Phox1 at the SRE and the basis for the selective activity of Paired class homeodomains in this context, we performed a detailed mutagenesis of the Phox1 homeodomain [9].

Anatomical context of PRRX1

• We have previously shown in focal adhesion kinase null cells, that tetracycline induced expression of focal adhesion kinase upregulated expression of LPP(2) and now show upregulation of palladin, and paired-related homeobox gene-1 protein [10].
• A10 SMCs cultured on native type I collagen showed low levels of Prx1 and Prx2 mRNA expression, whereas cells cultured on denatured collagen showed higher levels of expression of both genes [11].
• Polymorphism of the NADH/NADPH oxidase p22 phox gene in patients with coronary artery disease [12].
• The Phox homology (PX) domain has recently been reported to bind to phosphoinositides, and some PX domains can localize to endosomes in vivo [13].
• Reconstitution with C5a, a known ROS activator, enhanced the assembly of phox complex on the phagosomes as well as the production of ROS that inhibited the growth of MTB [14].

Associations of PRRX1 with chemical compounds

• In contrast, substitution of a lysine residue in the N-terminal arm of the Phox1 homeodomain appeared to abolish DNA binding without affecting activity in vivo [9].
• Enzymatic deglycosylation with alpha-mannosidase converted PRX1 and PRX2 to immunoreactive products migrating in mobility shift polyacrylamide gels at the positions of PRX2 and PRX3, respectively [15].
• Angiotensin II, focal adhesion kinase, and PRX1 enhance smooth muscle expression of lipoma preferred partner and its newly identified binding partner palladin to promote cell migration [10].
• Structural and Membrane Binding Analysis of the Phox Homology Domain of Phosphoinositide 3-Kinase-C2{alpha} [16].
• Aldolase bound with high affinity to a tryptophan-containing acidic sequence in SNX9 located close to its Phox homology domain, thereby blocking the membrane binding activity of SNX9 [17].

Other interactions of PRRX1

• Human PRRX1 and PRRX2 genes: cloning, expression, genomic localization, and exclusion as disease genes for Nager syndrome [18].
• A constitutive elevation of prx1 mRNA and protein was observed in Keap1 knock-out cells [1].
• We show that this protein, termed SPIN, interacts with SRF and Phox1 in vitro and in vivo [6].
• We report here the fusion between the NUP98 gene and another homeobox gene PMX1 in a case of human AML with a t(1;11)(q23;p15) translocation [2].
• Furthermore, Prx1 and TN-C promoter activities were significantly higher in FPAH vs. normal SMCs [19].

Analytical, diagnostic and therapeutic context of PRRX1

• Here, we report the identification, purification, and molecular cloning of a human protein that promotes the formation of stable higher-order complexes of SRF and Phox1 [6].
• To begin to elucidate how Prx1 and Prx2 are regulated and function in the adult vasculature, in situ hybridization studies were performed [11].
• Although the antioxidant function of Prx1 is expected to affect the radiotherapy response of lung cancer, the physiologic significance of its peroxidase activity in irradiated cells is unclear because the catalytic Cys52 is easily inactivated by ROS due to its overoxidation to sulfinic or sulfonic acid [4].
• The results of in vitro binding analysis and co-immunoprecipitation analysis in COS-7 cells show that the Src homology (SH) 3 domain of PLC-gamma1 binds to the proline-rich motif within the Phox homology (PX) domain of PLD2 [20].
• METHODS: Rat pancreatic islets or clonal rat BRIN BD11 beta cells were incubated in the presence of glucose, palmitic acid or pro-inflammatory cytokines for periods between 1 and 24 h. p47( phox ) production was determined by western blotting [21].

References