Transcription Factor Activating Protein-2β: A Positive Regulator of Monocyte Chemoattractant Protein-1 Gene Expression

Abstract

We previously reported an association between the activating protein (AP)-2beta transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with a disease-susceptible allele of AP-2beta showed stronger AP-2beta expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2beta leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study, we found that overexpression of AP-2beta in 3T3-L1 adipocytes accelerated the promoter activity of monocyte chemoattractant protein-1 (MCP-1) and subsequently increased both mRNA and protein expression and protein secretion. Furthermore, knockdown of endogenous AP-2beta by RNA interference reduced the mRNA and the protein expression of MCP-1. EMSAs and chromatin immunoprecipitation assays revealed specific binding of AP-2beta to MCP-1 promoter regions, in vitro and in vivo. Additionally, site-directed mutagenesis of the AP-2 binding site located at -137 to -129 relative to the transcription start site markedly diminished MCP-1 promoter activity, whereas other putative AP-2 binding sites did not. Our results clearly show that AP-2beta directly enhanced MCP-1 secretion by binding to its promoter. Thus, we propose that AP-2beta positively regulates MCP-1 expression; subsequently contributes to the infiltration of macrophages to adipose tissue; and leads to insulin resistance, type 2 diabetes, and cardiovascular diseases.