Disease relevance of Apex1

• Here we show the absence of mutations in the cDNA of the remaining Apex allele, a further suggestive indication of haploinsufficiency and its resulting predisposition to skin cancer [1].
• In this study we evaluated the role of asbestos, a prototypic model of chronic fibrotic lung disease, in Ref-1 expression and activity [2].
• The deduced amino acid sequence of mouse APEX nuclease exhibits a significant homology to those of exonuclease III of E. coli and ExoA protein of Streptococcus pneumoniae and an intensive homology with that of bovine AP endonuclease 1 [3].
• Restriction of multiple divergent retroviruses by Lv1 and Ref1 [4].
• Two further activities, Ref1, which acts on MLV, and Lv1, which acts on lentiviruses, have been identified in other mammalian species [5].

High impact information on Apex1

• Genetic interaction between HAP1/REF-1 and p53 [6].
• Interestingly, Stat3-C also upregulated the redox-associated protein redox factor-1 (Ref-1) and reduced apoptosis in liver following Jo2 injection by suppressing oxidative stress and redox-sensitive caspase-3 activity [7].
• The impaired MCK-E box binding activities resulted from abnormal myogenin-Jun-D complexes, and were normalized by the addition of Jun-D, dithiothreitol or Ref-1, a nuclear redox protein [8].
• The relationship between the redox and DNA repair activities of Ref-1 is intriguing; both activities have been suggested to play an important role in the cellular response to oxidative stress [9].
• 5. These findings demonstrate that Ref-1 is essential for early embryonic development [9].

Chemical compound and disease context of Apex1

• The APEX nuclease-depressed glioma cells became more sensitive to methyl methanesulfonate and hydrogen peroxide than the control cells or the APEX nuclease-overexpressed cells [10].

Biological context of Apex1

• The Trp53 and Apex heterozygous conditions altered the skin tumor spectrum to more poorly differentiated forms in all Xpc genotypes [1].
• The genomic sequence of the Apex gene was 2.14 kb in length and contained four exons [11].
• Developmental expression of APEX nuclease, a multifunctional DNA repair enzyme, in mouse brains [12].
• The amino acid sequence of rat APEX nuclease has 98.4% identity with mouse APEX nuclease [13].
• Unlike Ref-1 null mice, which die very early in embryonic development, homozygous ref-1(C64A) mice are viable, they survive to normal life expectancy, and they display no overt abnormal phenotype [14].

Anatomical context of Apex1

• Postnatal developmental changes of Apex mRNA expression in the testis and thymus were further studied [13].
• These data indicate that diminution of AP endonuclease has a significant effect on spontaneous mutagenesis in somatic and germ line cells [15].
• In this study we demonstrate that the redox factor APE/Ref-1 acts as a key signaling intermediate in response to CD40-mediated B cell activation [16].
• In this study, NIH 3T3 and HeLa cells were used to determine whether heat shock induces the AP-1 transcription factor via signaling pathways involving Ref-1 [17].
• These findings suggest that an exposure associated with fibrotic lung disease, i.e., asbestos, modulates accumulation of nuclear Ref-1 in macrophages, and that this effect is mediated by an oxidant stimulus [2].

Associations of Apex1 with chemical compounds

• Cysteine 64 of Ref-1 is not essential for redox regulation of AP-1 DNA binding [14].
• Recombinant mouse MUTYH (mMUTYH) efficiently excised adenine opposite 8-oxoG and prevented mouse AP endonuclease (mAPEX1) from incising the generated AP site [18].
• Additionally, an increase in nuclear Ref-1 could be induced by treating the cells with an oxidant-generating stimulus (iron loading plus PMA) and inhibited by diphenyleneiodonium chloride, an inhibitor of NADPH oxidase [2].
• These results demonstrate that dual activation of Ras/phosphoinositide 3-kinase and AP-1 cascades, which are mediated by Ref-1, is an essential component of the Grx2 mechanism of action [19].
• Young (4- to 6-month-old) and aged (24- to 28-month-old) mice were exposed to 2-nitropropane (2-NP), a DNA oxidizing agent, and the ability to induce DNA polymerase beta (beta-pol) and AP endonuclease (APE) was determined [20].

Physical interactions of Apex1

• These results indicate that heat shock activates c-Fos/c-Jun gene expression and AP-1 DNA binding and suggests that redox-sensitive signal transduction pathways involving Ref-1 may mediate heat-induced alterations in AP-1 activation [17].

Regulatory relationships of Apex1

• The ability of Ref-1 from heated cells to stimulate AP-1 DNA binding was abolished by chemical oxidation and restored by chemical reduction [17].

Other interactions of Apex1

• We also documented previously increased predisposition to UV radiation-induced skin cancers in Xpc-/- Apex+/- mice [1].
• Deletion analysis of a fragment containing the entire mouse Apex gene suggested that cis-acting elements driving in the direction of Osgep are widely distributed in the mApex gene, in the antisense orientation [21].
• Expression of the mammalian major apurinic/apyrimidinic (AP) endonuclease (designated as APEX nuclease, or HAP1, APE or Ref-1 gene product) during mouse brain development was investigated by in situ and northern blot hybridizations [12].
• Deletion of the previously defined redox-sensitive or the AP endonuclease domains of Ref-1 significantly decreased NF-kappaB transcriptional activation and endothelial cell survival [22].
• We have also found that two cellular thiol-reactive proteins, thioredoxin and Ref-1, work effectively and synergistically for activation of the Runt domain [23].

Analytical, diagnostic and therapeutic context of Apex1

• To investigate the physiological function of Ref-1, we used a gene targeting strategy to generate mice lacking a functional ref-1 gene [9].
• The Apex gene locus was mapped to mouse chromosome 14C2-D1 using in situ hybridization [24].
• Cloning, sequence analysis, and chromosomal assignment of the mouse Apex gene [24].
• Subsequently, an AP endonuclease or AP lyase activity incises the abasic site, followed by short-patch gap-filling, excision of the base-free sugar-phosphate residue, and ligation [25].
• Immunohistochemistry showed the nuclear expression of APE/Ref-1 in the entire region of the control brains [26].

References