Lead-induced upregulation of the heme-regulated eukaryotic initiation factor 2alpha kinase is compromised by hemin in human K562 cells.
Expression and kinase activity of the heme-regulated-eIF-2alpha 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.
Sarkar
Angshuman
A
Department of Biotechnology, University of Pune, Pune 411 007, India.
Kulkarni
Abhijeet
A
Chattopadhyay
Samit
S
Mogare
Devraj
D
Sharma
Kiran K
KK
Singh
Kamini
K
Pal
Jayanta K
JK
D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D041905:Erythroid Cells / Q000187:drug effects; D006427:Hemin / Q000378:metabolism*; D006454:Hemoglobins / Q000096:biosynthesis; D006801:Humans; D006979:Hyperthermia, Induced; D020014:K562 Cells; D007854:Lead / Q000494:pharmacology* / Q000633:toxicity; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000235:genetics*
D006454:Hemoglobins; D012333:RNA, Messenger; D007854:Lead; D006427:Hemin; D019892:eIF-2 Kinase