IDENTIFICATION OF NUCLEAR REGULATORY PROTEINS FOR THE INSULIN-RECEPTOR GENE

The mature insulin receptor (IR) is a transmembrane glycoprotein composed of two alpha and two beta subunits linked by disulfide bonds. The alpha subunit is extracellular and contains the binding site for the hormone, whereas the beta subunit contains a cytoplasmic tyrosine kinase domain that is regulated by insulin. Although the IR is ubiquitously expressed, very little is known about the molecular mechanisms regulating the level of IR protein or gene expression, Recently, the regulatory region of the human IR gene has been sequenced and analyzed by several groups. It is extremely GC-rich and spans over 1800 bp, between an Alu sequence at the 5' end and the JR translational initiation codon (AUG), It has neither a TATA box nor a CAAT box, reflecting the common features for constitutively expressed genes (so-called housekeeping genes). Herein, we have analyzed the regulatory region of the IR gene using a gel retardation assay combined with DNase I footprinting, Using these techniques we have identified two nuclear binding proteins that specifically interact with unique poly (dA-dT) tracts of the IR gene that have transcriptional activity. These nuclear binding proteins increased in cells that express IR mRNA and protein suggesting that are involved in the molecular mechanisms that control IR gene expression in target tissues.