INTERACTION OF STAT5 DIMERS ON 2 LOW-AFFINITY BINDING-SITES MEDIATES INTERLEUKIN-2 (IL-2) STIMULATION OF IL-2 RECEPTOR-ALPHA GENE-TRANSCRIPTION

Stimulation of the interleukin 2 receptor alpha (IL-2R alpha) gene by IL-2 is important for the proliferation of antigen-activated T lymphoc ytes. IL-2 regulates IL-2R alpha transcription via a conserved 51-nucl eotide IL-2 responsive enhancer. Mouse enhancer function depends on co operative activity of three distinct sites. Two of these are weak bind ing sites for IL-2-activated STATE (signal transducer and activator of transcription) proteins, and mutational analysis indicates that bindi ng of STAT5 to both sites is required for IL-2 responsiveness of the e nhancer. The STATE dimers interact to form a STATE tetramer. The effic iency of tetramerization depends on the relative rotational orientatio n of the two STAT motifs on the DNA helix. STAT5 tetramerization on en hancer mutants correlates well with the IL-2 responsiveness of these m utants. This provides strong evidence that interactions between STAT d imers binding to a pair of weak binding sites play a biological role b y controlling the activity of a well characterized, complex cytokine-r esponsive enhancer.