MOUSE INTERLEUKIN-2 RECEPTOR-ALPHA GENE-EXPRESSION - INTERLEUKIN-1 AND INTERLEUKIN-2 CONTROL TRANSCRIPTION VIA DISTINCT CIS-ACTING ELEMENTS

We have shown that interleukin-1 (IL-1) and IL-2 control IL-2 receptor alpha (IL-2R alpha) gene transcription in CD4(-)CD8(-) murine T lymphocyte precursors, Here we map the cis acting elements that mediate interleukin responsiveness of the mouse IL-2R alpha gene using a thymic lymphoma-derived hybridoma (PC60), The transcriptional response of the IL-2R alpha gene to stimulation by IL-1 + IL-2 is biphasic, IL-1 induces a rapid, protein synthesis-independent appearance of IL-2R alpha mRNA that is blocked by inhibitors of NF-kappa B activation, It also primes cells to become IL-2 responsive and thereby prepares the second phase, in which IL-2 induces a 100-fold further increase in IL-2R alpha transcripts. Transient transfection experiments show that several elements in the promoter-proximal region of the IL-2R alpha gene contribute to IL-1 responsiveness, most importantly an NF-kappa B site conserved in the human and mouse gene, IL-2 responsiveness, on the other hand, depends on a 78-nucleotide segment 1.3 kilobases upstream of the major transcription start site, This segment functions as an IL-2-inducible enhancer and lies within a region that becomes DNase I hypersensitive in normal T cells in which IL-2R alpha expression has been induced, IL-2 responsiveness requires three distinct elements within the enhancer. Two of these are potential binding sites for STAT proteins.