FOXO1 Up-Regulates Human L-selectin Expression through Binding to a Consensus FOXO1 Motif

Abstract

L-selectin plays important roles in lymphocyte homing and leukocyte rolling. Mounting evidence shows that it is involved in many disease entities including diabetes, ischemia/reperfusion injuries, inflammatory diseases, and tumor metastasis. Regulation of L-selectin at protein level has been well characterized. However, the regulation of human L-selectin transcription remains largely unknown. To address transcriptional regulation of L-selectin, we cloned 1088 bp 5′ of the start codon ATG. Luciferase analysis of the serial 5′ deletion mutants located the core promoter region at –288/–1. A major transcription initiation site was mapped at –115 by 5′RACE. Transcription factors Sp1, Ets1, Mzf1, Klf2, and Irf1 bind to and transactivate the L-selectin promoter. Significantly, FOXO1 binds to a FOXO1 motif, CCCTTTGG, at –87/–80, and transactivates the L-selectin promoter in a dose-dependent manner. Over-expression of a constitutive-active FOXO1 increased the endogenous L-selectin expression in Jurkat cells. We conclude that FOXO1 regulates L-selectin expression through targeting its promoter.