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

Granzyme B serine protease is found in the granules of activated cytot oxic T cells and in natural and lymphokine-activated killer cells, Thi s protease plays a critical role in the rapid induction of target cell DNA fragmentation, The DNA regulatory elements that are responsible f or the specificity of granzyme B gene transcription in activated T-cel ls reside between nt -148 and +60 (relative to the transcription start point at +1) of the human granzyme B gene promoter. This region conta ins binding sites for the transcription factors Ikaros, CBF, Ets, and AP-1. Mutational analysis of the human granzyme B promoter reveals tha t 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 ph ytohemagglutinin-activated peripheral blood lymphocytes, whereas mutat ion of the Ets binding site does not affect promoter activity in these cells.