AP-1 regulates the basal and developmentally induced transcription of the CD11c leukocyte integrin gene.
The p150,95 integrin (CD11c/CD18) mediates leukocyte/endothelium interactions during inflammatory reactions and certain CTL-target interactions, and is also a receptor for fibrinogen, LPS, and the complement component iC3b. CD11c/CD18 is expressed primarily on cells of the myeloid 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 binding 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 well as between B lineage-derived cells. The involvement of the AP1-60 element in DNA-protein interactions was confirmed by means of in vivo footprinting experiments, and its functionality was demonstrated by trans activation of the CD11c promoter by c-Jun. Site-directed mutagenesis of AP1-60 greatly reduced the basal CD11c promoter activity in myeloid and B cells. Furthermore, mutations at AP1-60 inhibited the induction of the CD11c promoter activity during the PMA-triggered U937 cell differentiation, pointing out a key role for the AP-1 transcription factor complex in both the basal and the developmentally regulated expression of the p150,95 leukocyte integrin. The involvement of AP-1 in the transcription of the CD11c gene raises the possibility of altering leukocyte integrin expression by pharmacologic means and will greatly contribute to the characterization of the intracellular signals controlling the expression of leukocyte adhesion molecules.
López-Rodríguez
C
C
Hospital of the Princesa, Madrid, Spain.
Kluin-Nelemans
H C
HC
Corbí
A L
AL
D001483:Base Sequence; D005786:Gene Expression Regulation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000187:drug effects / Q000235:genetics*; D004915:Leukemia, Erythroblastic, Acute; D015479:Leukemia, Myelomonocytic, Acute; D016403:Lymphoma, Large B-Cell, Diffuse; D008969:Molecular Sequence Data; D018808:Transcription Factor AP-1 / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D016167:Integrin alphaXbeta2; D018808:Transcription Factor AP-1