Disease relevance of Eif2ak1

• Results showed an inhibition of papilloma number in both restricted groups and the inhibition was greatest in the HCR mice [1].
• HCR, previously identified as alpha-helix coiled-coil rod homologue, is one of the psoriasis vulgaris (PV) candidate genes [2].

High impact information on Eif2ak1

• Expression of a kinase-defective Raf-1 mutant (craf301) or a regulatory domain fragment (HCR) inhibited serum-induced NIH/3T3-cell proliferation and raf transformation even more efficiently [3].
• We propose that an equilibrium state exists between Gadd34/PP1c and the opposing heme-regulated inhibitor kinase during hemoglobin synthesis in the reticulocyte [4].
• However, reactive oxygen species are involved only in HRI activation by arsenite [5].
• While autophosphorylation is essential for the activation of HRI, the phosphorylation status of HRI activated by different stresses is different [5].
• The contributions of HRI in various stress responses were assessed with the aid of HRI-null reticulocytes and fetal liver erythroid cells [5].

Biological context of Eif2ak1

• Heme-regulated inhibitor kinase-mediated phosphorylation of eukaryotic translation initiation factor 2 inhibits translation, induces stress granule formation, and mediates survival upon arsenite exposure [6].
• We have demonstrated that HRI in reticulocytes and fetal liver nucleated erythroid progenitors is activated by oxidative stress induced by arsenite, heat shock, and osmotic stress but not by endoplasmic reticulum stress or nutrient starvation [5].
• Study of the kinetics showed that the HRI kinase reaction follows classical Michaelis-Menten kinetics with respect to ATP but sigmoidal kinetics and positive cooperativity between subunits with respect to the protein substrate (eIF2alpha) [7].
• All constructs that contained a fully active HCR were expressed in approximately a copy-dependent manner, suggesting that transgene expression was independent of integration position [8].
• We show that the liver-specific expression of all four genes in the human apolipoprotein (apo) E/C-I/C-IV/C-II gene cluster in transgenic mice is determined by the coordinate action of two distinct hepatic control regions (HCR) [9].

Anatomical context of Eif2ak1

• The heme-regulated eukaryotic initiation factor 2alpha (eIF2alpha) kinase (heme-regulated inhibitor (HRI)) is activated by heme deficiency in reticulocytes and plays an important role in translational control in these cells [10].
• Previously, HRI was cloned from rabbit reticulocytes and rat brain, but a heme-regulated eIF2alpha kinase activity has only been purified from erythroid cells [10].
• Among many differentially expressed genes, eIF2alpha kinase, a heme regulated inhibitor was down-regulated in ovarian epithelium cancer [11].
• Of the four protein kinases known to phosphorylate eukaryotic translation initiation factor 2alpha, only the heme-regulated inhibitor kinase (HRI) was required for the translational inhibition in response to arsenite treatment in mouse embryonic fibroblasts [6].
• Two hybridoma clones secreting HRI-specific antibodies (mAB A and mAB F) were obtained [12].

Associations of Eif2ak1 with chemical compounds

• In vivo studies elucidated a fundamental requirement for HRI in murine survival upon acute arsenite exposure [6].
• Finally, we found that HRI is inhibited by bilirubin at physiological/pathological levels (IC(50) = 20 microM) [7].
• The function of HCR was analyzed in transgenic mice and turned out to be a position-specific regulatory element of human, setting the precise anterior boundary of expression in transgenic embryos; at day 12.5 post-coitum a distinct anterior limit of expression was noted at the level of C5 in neural tube and spinal ganglia in transgenic embryos [13].
• CF1 mice and BN, HCR and HCS rats fed 0.1% BSA for 56 days also did not produce circulating antibodies during ingestion, and almost all were hyporesponsive after parenteral challenge [14].

Other interactions of Eif2ak1

• Here, we found that the rate of dissociation for Fe(III)-protoporphyrin IX was much higher for full-length HRI (1.5 x 10(-)(3) s(-)(1)) than for myoglobin (8.4 x 10(-)(7) s(-)(1)) or the alpha-subunit of hemoglobin (7.1 x 10(-)(6) s(-)(1)), demonstrating the heme-sensing character of HRI [7].

Analytical, diagnostic and therapeutic context of Eif2ak1

• HRI from reticulocyte lysates could be quantitatively removed by immunoprecipitation with mAB F, and such HRI-depleted lysates were able to maintain protein synthesis under conditions of heme deficiency [12].
• Both antibodies immunoprecipitated biosynthetically labeled as well as phosphorylated HRI in reticulocyte lysates and also recognized denatured HRI in a Western blot [12].
• Its behaviour on gel filtration is similar to that of HCR, while its behaviour on anion exchange resembles that of certain phosphorylated species of HCR [15].
• In situ hybridization studies showed that the HCR directed apoE and apoC-I transgene expression in hepatocytes [16].

References