GABP COOPERATES WITH C-MYB AND C EBP TO ACTIVATE THE NEUTROPHIL ELASTASE PROMOTER/

Neutrophil elastase (NE) is a serine protease that is transcriptionall y regulated during early myeloid differentiation. The murine NE (mNE) promoter contains functionally important c-Myb, C/EBP, and ets binding sites. Deletion of the ets site reduced promoter activity by 90%. Alt hough the ets transcription factor, PU.1, bound to this ets site, it o nly modestly activated the mNE promoter. Here, we show that a second t ranscription factor from myeloid cells - GABP - binds to the mNE ets s ite but strongly activates the mNE promoter. GABP is a heteromeric tra nscription factor complex that consists of GABP alpha, an ets factor, and GABP beta, a Notch-related protein. GABP alpha bound to the mNE et s site and, in turn, recruited GABP beta to form a transcriptionally a ctive complex. GABP alpha and PU,1 competed with each other for bindin g to the mNE ets site. GABP increased the activity of the mNE promoter sevenfold in U937 myeloid cells. GABP cooperated with c-Myb and C/EBP alpha to activate the mNE promoter more than 85-fold in otherwise non permissive, nonhematopoietic NIH 3T3 cells. Thus, GABP binds to the cr ucial mNE promoter ets site and powerfully activates its expression al one and in cooperation with the transcription factors c-Myb and C/EBP. (C) 1997 by The American Society of Hematology.