AP-1 REGULATES THE BASAL AND DEVELOPMENTALLY INDUCED TRANSCRIPTION OFTHE CD11C LEUKOCYTE INTEGRIN GENE

The p150,95 integrin (CD11c/CD18) mediates leukocyte/endothelium inter actions during inflammatory reactions and certain CTL-target interacti ons, and is also a receptor for fibrinogen, LPS, and the complement co mponent iC3b. CD11c/CD18 is expressed primarily on cells of the myeloi d lineage and activated B lymphocytes, and is an important diagnostic marker for hairy cell leukemia. To identify the transcription factors and cis-acting elements involved in the regulated expression of CD11c/ CD18 during myeloid cell differentiation and B lymphocyte activation, we have performed structural and functional analysis on the CD11c gene promoter. Electrophoretic mobility shift assays identified an AP-1 bi nding site (AP1-60) within the proximal promoter region and evidenced differences in the pattern of the Fos family members bound to the AP1- 60 element in undifferentiated and differentiated myeloid cells, as we ll as between B lineage-derived cells. The involvement of the AP1-60 e lement in DNA-protein interactions was confirmed by means of in vivo f ootprinting experiments, and its functionality was demonstrated by tra ns activation of the CD11c promoter by c-Jun. Site-directed mutagenesi s of AP1-60 greatly reduced the basal CD11c promoter activity in myelo id and B cells. Furthermore, mutations at AP1-60 inhibited the inducti on of the CD11c promoter activity during the PMA-triggered U937 cell d ifferentiation, pointing out a key role for the AP-1 transcription fac tor complex in both the basal and the developmentally regulated expres sion of the p150,95 leukocyte integrin. The involvement of AP-1 in the transcription of the CD11c gene raises the possibility of altering le ukocyte integrin expression by pharmacologic means and will greatly co ntribute to the characterization of the intracellular signals controll ing the expression of leukocyte adhesion molecules.