Molecular Mechanisms Regulating Matrix Metalloproteinases

Christina      Piperi; Athanasios      G. Papavassiliou

Abstract

The family of matrix metalloproteinases (MMPs) comprises 24 multidomain enzymes with a zinc-dependent activity. Their structural diversity over the archetypal domain organization confers variable biological function to these molecules ranging from cellular homeostasis and control of tissue turnover to implication in multiple pathological conditions such as inflammation, arthritis, cardiovascular disease and cancer. MMP expression and activity exhibits high tissuespecies- and signal-specificity and involves multiple regulatory mechanisms that co-ordinate zymogen activation, endogenous inhibition and gene transcription. In this article, we provide an overview of the molecular mechanisms that regulate MMPs gene expression at transcriptional and post-transcriptional level through integration of signals from multiple pathways to cis-acting elements present in MMP promoters, epigenetic modifications, mRNA stability mechanisms and microRNA modulation. Loss of MMP activity through mutations and single nucleotide polymorphisms is further discussed in the context of disease susceptibility.

Keywords: Matrix metalloproteinases, gene expression, epigenetics, microRNA, mutation, polymorphisms, multidomain enzymes, zinc-dependent activity, zymogen activation, molecular mechanisms, gene transcription, epigenetic modifications, nucleotide polymorphisms, cellular homeostasis