Stress-induced overexpression of the heme-regulated eIF-2alpha kinase is regulated by Elk-1 activated through ERK pathway

The heme-regulated eIF-2alpha kinase, also called the heme-regulated inhibitor (HRI), is activated under various cytoplasmic stresses in reticulocytes leading to inhibition of initiation of protein synthesis. Our previous studies indicated that the promoter activity and expression of the human HRI (hHRI) increase in human K562 cells during heat shock and lead exposure. Contrary to this, hemin chloride which inactivates the kinase, downregulates HRI expression. Here, we attempted to understand the mechanism of regulation of hHRI expression in the lead- and hemin-exposed cells. Our results demonstrate the involvement of two transcription factors, Elk-1 and MZF-1 in regulating HRI expression. Chromatin immunoprecipitation assays established further that Elk-1 is involved in upregulating HRI expression during stress along with a co-activator p300, while MZF-1 along with HDAC-1 is instrumental in its downregulation during hemin treatment. We also demonstrate the involvement of ERK pathway in activating Elk-1 during stress resulting in an over expression of hHRI.