Disease relevance of EIF2AK1

• Additionally, native complexes of HRI with p50(cdc37) were detected in cultured K562 erythroleukemia cells [1].
• Cloning of hHRI, human heme-regulated eukaryotic initiation factor 2alpha kinase: down-regulated in epithelial ovarian cancers [2].
• Here we report the essential role of HRI in 2 mouse models of human rbc disorders, namely erythropoietic protoporphyria (EPP) and beta-thalassemia [3].
• To study further the regulation of the heme-regulated eIF-2 alpha kinase (HRI), we have produced functional wild type HRI using the baculovirus expression system [4].
• We therefore studied whether combinations of the HRI lovastatin with standard chemotherapeutic agents would augment apoptosis in colon cancer cells [5].

High impact information on EIF2AK1

• In both cases, lack of HRI adversely modifies the phenotype: HRI deficiency exacerbates EPP and renders beta-thalassemia embryonically lethal [3].
• However, to date, HRI has not been implicated in the pathogenesis of any known human disease or mouse phenotype [3].
• HRI is also activated by a number of cytoplasmic stresses other than heme deficiency, including oxidative stress and heat shock [3].
• The high levels of HRI in reticulocytes indicate that its major physiological role is the regulation of protein synthesis, particularly of hemoglobin, according to the concentration of heme in these cells [6].
• HRI is activated under conditions of heme deficiency in immature erythroid cells, and its activity is inhibited by heme [6].

Biological context of EIF2AK1

• These results suggest that p50(cdc37) provides an activity essential to HRI biogenesis via a process regulated by nucleotide-mediated conformational switching of its partner Hsp90 [1].
• Cyp40 was a salt labile component of Hsp90 complexes formed with the full-length, catalytic domains, and N-terminal catalytic lobes of Lck and HRI [7].
• Additionally, scanning alanine mutagenesis identified four amino acid residues at the N-terminus of Cdc37 that are critical for high-affinity binding of Cdc37 to client HRI molecules [8].
• The hHRI gene is 2,887 bp in length and the amino acid sequence deduced from the cDNA clone encodes a protein of 630 amino acids with molecular mass of 73 kDa [2].
• The down-regulation of hHRI was also confirmed in other ovarian cancer tissues by Northern blot hybridization [2].

Anatomical context of EIF2AK1

• The resulting increase of fibrinolytic activity of endothelial cells may contribute to the beneficial effects of HRI in the progression of atherosclerosis [9].
• HRI mRNA is present at low levels in uninduced mouse erythroleukemic (MEL) cells and human K562 cells and accumulates to higher levels upon induction [10].
• The effect of HRI was associated with a disruption of cellular actin filaments without modification of microtubules [9].
• HRI is present in the bone marrow and peripheral blood of both nonanemic and anemic rabbits but not in any of the other tissues tested [10].
• In this study, we show that eIF-2B activity was inhibited in parental CHO cell extracts upon addition of purified reticulocyte heme-regulated inhibitor (HRI), an eIF-2 alpha kinase that phosphorylates Ser-51 [11].

Associations of EIF2AK1 with chemical compounds

• A C-terminal truncated mutant of p50(cdc37) inhibited HRI's activation, prevented the interaction of Hsp90 with HRI, and bound to HRI irrespective of geldanamycin treatment [1].
• Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI [12].
• Novobiocin specifically inhibited the maturation of the heme-regulated eIF2alpha kinase (HRI) in a concentration-dependent manner [13].
• In addition, autophosphorylation of Thr485 was necessary for arsenite-induced activation of the eIF2alpha kinase activity of HRI, while autophosphorylation at Thr483 was not required for activation by arsenite [12].
• The addition of 3-amino-1,2,4-triazole (AT), an inhibitor of heme biosynthesis, to the induction medium markedly reduced HRI mRNA accumulation [10].

Regulatory relationships of EIF2AK1

• These results suggest that heme-controlled repressor is activated in heat-shocked cells and that eIF-2 alpha phosphorylation limits mRNA translation even after partial recovery of protein synthesis [14].

Other interactions of EIF2AK1

• Phosphorylation of eukaryotic initiation factor 2 by heme-regulated inhibitor kinase-related protein kinases in Schizosaccharomyces pombe is important for fesistance to environmental stresses [15].

Analytical, diagnostic and therapeutic context of EIF2AK1

• Isoelectric focusing analysis of eIF2alpha followed by detection using anti-eIF2alpha and anti-phosphotyrosine-specific antibodies demonstrated that PKR and HRI phosphorylated eIF2alpha-S51Y on Tyr in vivo [16].
• The predictive accuracy of hourly %VLFI (frequency-domain HRI variable obtained from nocturnal ECG Holter monitoring) was analysed by comparison with an hour-by-hour respiratory disturbances index assessed by complete polysomnography in 28 consecutive clinically suspected OSAHS patients for group 1 and in 35 patients for group 2 [17].
• These values were compared with the results obtained for a quantitative Western blot of HRI in the blood cell lysates of drug- and lead-induced anaemic rabbits [18].
• Results: Mean HRI value obtained in the control group was 0.415 (range 0.305 -0.555; median 0.402) [19].
• After adjustment, deployers with fair/poor SRH had an increased risk for hospitalization (hazard ratio [HRI, 1.6; 95% confidence interval [CI], 1.0,2.7); the risk was lower for those with good SRH (HR, 1.3; 95% CI,1.1,1.5) [20].

References