Regulation of the leukocyte integrin gene CD11c is mediated by AP1 and Ets transcription factors

Abstract

The leukocyte integrin gene, CD11c, encodes the α subunit of the p150,95 (CD11c·CD18) receptor. Expression of the CD11c gene is predominately seen in monocytes, but has also been detected in some B- and T-cell neoplasms and in some large-cell lymphomas of uncertain origin. To elucidate the molecular mechamisms that govern the expression of CD11c, we have cloned and characterized the promoter region of this gene. The DNase I footprint and mobility shift analyses revealed five sites within the −86 to +40 region that interact with nuclear proteins. The −62 to −44 region contains two consensus sequences for AP1 (referred to as AP1-1 and AP1-2) and were shown to bind purified c-jun protein. Co-transfection of c-fos and c-jun expression constructs with a CD11c promoter-CAT fusion into HL60 cells led to a 6.7-fold increase in CD11c promoter activity. We show that c-fos and c-jun mediate their effects through both AP1-1 and AP1-2 which function in an additive manner. Regions −42 to −34 and − 13 to −5 contain consensus sequences for Ets factors (referred to as Ets C and Ets A, respectively). Deletion of Ets C resulted in a significant reduction in phorbol ester-induced expression of CD11c, whereas deletion of Ets A led to only a modest loss in CD11c expression. We show that C Ets cooperates with the AP1 sites to regulate CD11c expression.