Regulating Expression of the Gene for Matrix Metalloproteinase-1 (Collagenase): Mechanisms that Control Enzyme Activity, Transcription, and mRNA Stability

Self Cite

Exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of pathological lesions in humans via activation of the aryl hydrocarbon receptor (AhR) pathway. It has become apparent that this pathway interacts with a variety of signaling pathways that are believed to be involved in mediating TCDD/AhR biological effects. Our hypothesis is that TCDD mediates these pathological lesions by directly altering the expression of genes involved in matrix deposition and remodeling and that the retinoic acid signaling pathway is involved in modulating TCDD-induced effects. Therefore, we examined the effect of TCDD and all-trans retinoic acid (atRA) on the expression of matrix metalloproteinase-1 (MMP-1, interstitial collagenase), one of the proteolytic enzymes that degrade type I collagen, in normal human keratinocytes. The data show that TCDD exposure results in increased MMP-1 expression in keratinocytes that is further enhanced by co-treatment with all-trans retinoic acid. TCDD-induced expression of MMP-1 appears to be mediated through two AP-1 elements in the proximal promoter of the MMP-1 gene. However, retinoic acid-mediated induction of keratinocyte MMP-1 is a result of both promoter activation and increased mRNA stability. These findings are the first to demonstrate TCDD-induced expression of MMP-1 and to demonstrate interactions between the TCDD/AhR and retinoic acid pathways on MMP-1 expression.Exposure to the polycyclic aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 1 results in a number of pathological lesions involving matrix deposition and tissue remodeling, including prostate and mammary tubule morphogenesis, palatal development, and tumor promotion (1-3). We hypothesize that TCDD mediates these pathological lesions by altering the expression of genes involved in matrix remodeling.Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the protein components of the extracellular matrix. MMP expression is integral to processes in skin remodeling and inappropriate expression and activity of MMPs is associated with a variety of pathologies such as rheumatoid arthritis and tumor metastasis (4 -6). Regulation of MMPs occurs primarily at the levels of transcription and activity (7). Investigation into MMP gene expression have identified several cis-and trans-acting factors that are involved in MMP-1 transcriptional activation, including several AP-1 sites and PEA-3 elements, that contribute to MMP-1 gene expression (8, 9).The primary mechanism of TCDD-induced changes in gene expression is through activation of the aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (Arnt) transcription pathway. AhR and its dimerization partner, Arnt, are members of the basic helix-loop-helix PAS (bHLH-PAS) domain family of transcription factors. Proteins in this family have diverse biological roles ranging from regulation of development, hypoxia signaling, and circadian rhythms (reviewed in Ref.

“…activate MMP-1 expression through the AP-1 elements in the proximal promoter region (7,27). As observed in Fig.…”

Section: Tcdd Activation Of Ap-1 Binding Activates Mmp-1 Expression-dmentioning

confidence: 63%

Section: Fig 3 Atra Abolishes Tcdd-induced Binding To the Cyp1a1mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Interaction between the Aryl Hydrocarbon Receptor and Retinoic Acid Pathways Increases Matrix Metalloproteinase-1 Expression in Keratinocytes

Murphy

Villano

Dorn

et al. 2004

Self Cite

“…U0126 had no effect on cAMP-dependent response element-driven luciferase expression from the RP5Ј promoter and was also without effect on the GRE-driven tyrosine aminotransferase gene. In contrast, U0126 did inhibit TPA-dependent TRE-driven luciferase expression in the RP5Ј reporter construct along with MMP-1, a gene known to be highly dependent upon AP-1 for its inducible activity by multiple stimuli (24).…”

Section: Identification Of a Novel Inhibitor Of Ap-1-driven Gene Actimentioning

confidence: 75%

Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase

Favata¹,

Horiuchi²,

Manos³

et al. 1998

2,832

2,077

We further demonstrate that the two compounds bind to ⌬N3-S218E/S222D MEK in a mutually exclusive fashion, suggesting that they may share a common or overlapping binding site(s). Quantitative evaluation of the steady state kinetics of MEK inhibition by these compounds reveals that U0126 has approximately 100-fold higher affinity for ⌬N3-S218E/S222D MEK than does PD098059. We further tested the effects of these compounds on the activity of wild type MEK isolated after activation from stimulated cells. Surprisingly, we observe a significant diminution in affinity of both compounds for wild type MEK as compared with the ⌬N3-S218E/S222D mutant enzyme. These results suggest that the affinity of both compounds is mediated by subtle conformational differences between the two activated MEK forms. The MEK affinity of U0126, its selectivity for MEK over other kinases, and its cellular efficacy suggest that this compound will serve as a powerful tool for in vitro and cellular investigations of mitogen-activated protein kinase-mediated signal transduction.

“…We chose to inhibit ERK, c-src tyrosine kinase, and protein kinase C pathways because of their involvement in MMP expression (21)(22)(23). Northern blot analysis showed that 24-h treatment with 5% CSE alone increased MMP-1 mRNA in SAECs (Fig.…”

Section: Cse Increases Mmp-1 In Airway Epithelialmentioning

confidence: 99%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

158

172

The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.