The KIR3DL1 gene is a member of killer immunoglobulin-like receptors family, which exhibits a variegated expression pattern in NK cells and subsets of CD4(+) and CD8(+) T cells. The E2F family of transcription factors plays a crucial role in the regulation of gene expression. The present study reports a naturally occurring point mutation (TITGGCGC -> TTCGGCGC) within a putative E2F binding site in the KIR3DL1 promoter in K562 cells. Interestingly, this mutation introduces a new methylation site. This study shows for the first time that E2F1 binds to the KIR3DL1 promoter in vivo. This point mutation and concomitantly altered methylation pattern within the E2F1 binding site abolishes their binding and reduces the promoter activity, while elevated expression of E2F1 correlates with increased promoter activity. Therefore, E2F1 contributes to the transcriptional activation of the KIR3DL1 gene. (c) 2008 Elsevier Inc. All rights reserved.