Lead-induced upregulation of the heme-regulated eukaryotic initiation factor 2α kinase is compromised by hemin in human K562 cells

Abstract

Expression and kinase activity of the heme-regulated-eIF-2α kinase or -inhibitor (HRI) are induced during cytoplasmic stresses leading to inhibition of protein synthesis. Using a reporter construct with HRI promoter, we have determined the promoter activity during heat-shock and lead toxicity in human K562 cells. These two conditions induced HRI promoter activity by 2- to 3-fold. Contrary to this, hemin, a suppressor of HRI kinase activity, downregulated HRI promoter activity and stimulated hemoglobin synthesis. Interestingly, when hemin-treated cells were transfected and exposed to lead, hemin compromised lead-effect substantially by downregulating HRI promoter activity, HRI transcription and HRI kinase activity. These results together suggest that heme signaling in relation to translation regulation is not only restricted to the cytoplasm (modulating HRI kinase activity) alone but it also spans to the nucleus modulating HRI expression. Hemin may thus be useful for alleviation of stress-induced inhibition of protein synthesis.