Identification of a Cigarette Smoke–Responsive Region in the Distal MMP-1 Promoter

Abstract

Tobacco-related diseases are leading causes of death worldwide, and many are associated with expression of matrix metalloproteinase-1 (MMP-1). We have reported extracellular signal-regulated kinase (ERK)1/2-dependent induction of MMP-1 by cigarette smoke in lung epithelial cells. Our objectives were to define regions of the human MMP-1 promoter required for activation by smoke, to identify differences in responses of the 1G/2G -1607 polymorphic promoters to smoke, and to identify relevant transcription factors whose activity in airway epithelial cells is increased by smoke. The responses of deletion and mutant promoter constructs were measured in transfected cells during exposure to cigarette smoke extract (CSE). DNA oligonucleotide arrays were used to identify transcription factors activated after smoke exposure. CSE activated the MMP-1 promoter, and this induction was prevented by PD98059 blockade of ERK1/2 phosphorylation. Deletion studies revealed the distal 1kb promoter region (-4438 to -3280 upstream of the transcription start site) is essential for CSE induction of MMP-1, and confers activation of a minimal promoter. Studies of 1G and 2G MMP-1 polymorphic promoter variants revealed higher 2G allele basal and CSE-responsive activities than the 1G allele. Cotransfection, mithramycin, and electrophoretic mobility shift assay studies identified activating and repressive roles for Sp1 and PEA3 transcription factors, respectively. Oligonucleotide DNA arrays confirmed activation of Sp1 and PEA3 by CSE. These data demonstrate that the MMP-1 promoter is a direct target of cigarette smoke in lung epithelial cells. This characterization of a smoke response region in the distal MMP-1 promoter has implications for smoking-related diseases such as cancer, heart disease, and emphysema.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Indeed, transgenic mice expressing human MMP1 develop changes resembling human emphysema (D'Armiento et al, 1992;Foronjy et al, 2003). The promoter of the MMP1 gene has a CSEresponsive element (Mercer et al, 2009) and a polymorphism in the MMP1 gene (G1607GG) has been linked to rapidly declining lung function in smokers (Wallace et al, 2012). Interestingly, MMP1 also exhibits a neurotropic function in that it sensitizes vagal C fibers to chronic cough.…”

The impact of emphysema in pulmonary fibrosis

“…Individual genetic backgrounds may also predispose to the development of CPFE. A polymorphism in the promoter of the matrix metalloproteinase-1 gene, for example, has been identified in smokers [25], and it is conceivable that such pathway might be dysregulated in patients with CPFE. A heterozygous mutation in SFTPC (the gene encoding surfactant protein C) has been reported in a nonsmoking young female with CPFE [26].…”

Matrix metalloproteinases in COPD

“…Further work has demonstrated that induction of MMP-1 by cigarette smoke is regulated at the promoter site, and ERK1/2 signalling is required. In addition, the proximal binding sites for transcription factor activator protein 1 (AP-1) is required for both baseline and cigarette smoke induced activation of the promoter [81].…”