Dna encoding the heme-regulated eukaryotic initiation factor 2.alpha.

Abstract

The cDNA which encodes heme-regulated eIF-2.alpha. kinase (HRI) has been cloned from a lambda Zap II cDNa of rabbit reticulocytes. The rabbit HRI cDNA is highly homologous to human HRI and hybridizes to the human HRI DNA under moderately stringent conditions. The rabbit HRI cDNA contains 2729 amino acids. In vitro translation of HRI mRNA transcribed from HRI cDNA yields a 90 kDa polypeptide with eIF-2.alpha. kinase activity. Since HRI is a potent inhibitor or protein synthesis, it is anti-proliferative in nature. In addition, the unusually high degree of homology of HRI to three protein kinases involved in the regulation of cell division suggests that HRI plays a direct role in the regulation of cell division. Since regulation of protein synthesis is vital of cell growth and differentiation, the cDNA can be inserted into cells to manipulate proliferation and differentiation, especially of cells that are proliferating in an uncontrolled manner of characterized by arrested differentiation, such as some of the types of cancers. Deletion mutants of HRI cDNA can be constructed that are insensitive to regulation by heme, which should be more effective than native HRI in its anti-viral and anti-proliferative action.