Interaction of STAT5 dimers on two 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-2Ralpha) gene by IL-2 is important for the proliferation of antigen-activated T lymphocytes. IL-2 regulates IL-2Ralpha transcription via a conserved 51-nucleotide IL-2 responsive enhancer. Mouse enhancer function depends on cooperative activity of three distinct sites. Two of these are weak binding sites for IL-2-activated STAT5 (signal transducer and activator of transcription) proteins, and mutational analysis indicates that binding of STAT5 to both sites is required for IL-2 responsiveness of the enhancer. The STAT5 dimers interact to form a STAT5 tetramer. The efficiency of tetramerization depends on the relative rotational orientation of the two STAT motifs on the DNA helix. STAT5 tetramerization on enhancer mutants correlates well with the IL-2 responsiveness of these mutants. This provides strong evidence that interactions between STAT dimers binding to a pair of weak binding sites play a biological role by controlling the activity of a well characterized, complex cytokine-responsive enhancer.
Meyer
W K
WK
Lymphocyte Biology Unit, Swiss Institute for Experimental Cancer Research (ISREC), 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland.
Reichenbach
P
P
Schindler
U
U
Soldaini
E
E
Nabholz
M
M
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D011485:Protein Binding; D015375:Receptors, Interleukin-2 / Q000235:genetics*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D004247:DNA