ERYTHROID EXPRESSION OF THE HEME-REGULATED EIF-2-ALPHA KINASE

The role of heme-regulated eIF-2 alpha kinase (HRI) in the regulation of protein synthesis in rabbit reticulocytes is well documented. Inhib itors of protein synthesis with properties similar to those of HRI hav e been described in some nonerythroid cell types, but it has not yet b een determined whether these eIF-2 alpha kinase activities are mediate d by HRI or one or more as yet uncharacterized kinases. We have studie d the expression of mRNA, polypeptide, and kinase activities of HRI in various tissues from both nonanemic and anemic rabbits. Our results i ndicate that HRI is expressed in an erythroid cell-specific manner. HR I is present in the bone marrow and peripheral blood of both nonanemic and anemic rabbits but not in any of the other tissues tested. HRI mR NA is present at low levels in uninduced mouse erythroleukemic (MEL) c ells and human K562 cells and accumulates to higher levels upon induct ion. The accumulation of HRI mRNA in differentiating MEL cells is depe ndent upon the presence of heme. The addition of 3-amino-1,2,4-triazol e (AT), an inhibitor of heme biosynthesis, to the induction medium mar kedly reduced HRI mRNA accumulation. Simultaneous addition of hemin an d AT to the dimethyl sulfoxide induction medium largely prevented the inhibition of HRI mRNA induction by AT. These findings indicate that H RI is expressed in an erythroid cell-specific manner and that the majo r physiologic role of HRI is in adjusting the synthesis of globins to the availability of heme.