c‐Myc inhibits CD11a and CD11c leukocyte integrin promoters

The c‐Myc transcription factor is an important regulator of cell growth and differentiation, and its gene repression ability seems to play a key role in Myc‐mediated cellular transformation. Since Myc overexpression has been associated with reduced expression of β1 and β2 integrins, we have investigated the role of c‐Myc on CD11a and CD11c transcription. c‐Myc inhibited CD11a and CD11c integrin promoter activity in co‐transfection experiments, and similar repression was obtained in cells where c‐Myc expression (KmycB) or activity (Rat‐1 c‐MycERTM) is inducible. The c‐Myc repression on the CD11c promoter was independent of the USF‐binding site (USF‐150), other putative Myc‐binding elements, or the integrity of the initiator (Inr)‐like sequence present at the major transcriptional start site. Analysis of deletion and mutant promoter constructs revealed that, in the absense of additional upstream cis‐acting elements, an AP‐1‐binding site at ‐60 (AP1‐60) is required for c‐Myc repressor activity. The c‐Myc repressor activity on both integrin promoters was abrogated by deletion of c‐Myc residues 106 – 143, a domain involved in Inr‐dependent transcriptional repression. These results demonstrate a direct effect of c‐Myc on integrin gene transcription and suggest the existence of a c‐Myc‐dependent mechanism for coupling leukocyte integrin expression to the cell proliferative state.