Initiation of protein synthesis requires the formation of a ternary complex among eIF-2, GTP, and the initiator met tRNA. The formation of this ternary complex represents the first regulated step in protein translation. While much is known about the regulation of protein translation through posttranslational modification of the alpha subunit of eIF-2, little is known about the transcriptional regulation of the three subunits of eIF-2. eIF-2alpha is a housekeeping gene whose activity is essential for all cells. The promoter structure of eIF-2alpha is similar to that of most housekeeping genes in that it is G+C rich, has multiple transcription start sites for known transcription factors. Basal transcription shows a two-fold dependence on the presence of a palindromic sequence immediately upstream of and overlapping the transcription start sites. The promoter of eIF-2 alpha is complex and contains at least eight in vitro footprints. The overall goal of this project is to understand in detail the mechanism by which eIF-2alpha is regulated. Although no human disease is known to be associated with abnormalities in the regulation of eIF-2alpha, an understanding of the regulation of this gene will be useful in elucidating the regulatory mechanisms utilized by housekeeping genes.
