IDENTIFICATION OF HUMAN GRANZYME-B PROMOTER REGULATORY ELEMENTS INTERACTING WITH ACTIVATED T-CELL-SPECIFIC PROTEINS - IMPLICATION OF IKAROS AND CBF BINDING-SITES IN PROMOTER ACTIVATION

Granzyme B serine protease is found in the granules of activated cytotoxic T cells and in natural and lymphokine-activated killer cells, This protease plays a critical role in the rapid induction of target cell DNA fragmentation, The DNA regulatory elements that are responsible for the specificity of granzyme B gene transcription in activated T-cells reside between nt -148 and +60 (relative to the transcription start point at +1) of the human granzyme B gene promoter. This region contains binding sites for the transcription factors Ikaros, CBF, Ets, and AP-1. Mutational analysis of the human granzyme B promoter reveals that the Ikaros binding site (-143 to -114) and the AP-1/CBF binding site (-103 to -77) are essential for the activation of transcription in phytohemagglutinin-activated peripheral blood lymphocytes, whereas mutation of the Ets binding site does not affect promoter activity in these cells.