Lead exposure and heat shock inhibit cell proliferation in human HeLa and K562 cells by inducing expression and activity of the heme-regulated eIF-2alpha kinase.

We have used human cell lines, namely, K562 and HeLa cells as model systems in understanding the mechanism of lead toxicity and heat shock, that may be mediated by the heme-regulated eIF-2alpha kinase which is also called the heme-regulated inhibitor (HRI). RT-PCR analysis using HRI-specific primers indicated a two- to three-fold increase in HRI expression in K562 and HeLa cells exposed to lead acetate and heat shock, respectively. Further, in vitro eIF-2alpha kinase assay indicated a two- to three-fold increase in HRI kinase activity during lead toxicity in K562 cells. This increase in HRI expression and its activity was accompanied by a significant decrease in cell proliferation and cell viability. This is therefore, the first report indicating that both heavy metal exposure and heat shock cause inhibition of protein synthesis not by activation of HRI alone but by its over-expression as well as activation. Our data indicate further that lead-induced inhibition of cell proliferation may be caused due to inhibition of protein synthesis resulted due to induced expression and activity of HRI.