Fanjul-Fernández Miriam, Folgueras Alicia R, Cabrera Sandra, López-Otín Carlos
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Biochim Biophys Acta. 2010 Jan;1803(1):3-19. doi: 10.1016/j.bbamcr.2009.07.004. Epub 2009 Jul 23.
Matrix metalloproteinases (MMPs) are a large family of zinc-endopeptidases which play important roles in multiple physiological and pathological processes. These enzymes are widely distributed in all kingdoms of life and have likely evolved from a single-domain protein which underwent successive rounds of duplication, gene fusion and exon shuffling events to generate the multidomain architecture and functional diversity currently exhibited by MMPs. Proper regulation of these enzymes is required to prevent their unwanted activity in a variety of disorders, including cancer, arthritis and cardiovascular diseases. Multiple hormones, cytokines and growth factors are able to induce MMP expression, although the tissue specificity of the diverse family members is mainly achieved by the combination of different transcriptional control mechanisms. The integration of multiple signaling pathways, coupled with the cooperation between several cis-regulatory elements found at the MMP promoters facilitates the strict spatiotemporal control of MMP transcriptional activity. Additionally, epigenetic mechanisms, such as DNA methylation or histone acetylation, may also contribute to MMP regulation. Likewise, post-transcriptional regulatory processes including mRNA stability, protein translational efficiency, and microRNA-based mechanisms have been recently described as modulators of MMP gene expression. Parallel studies have led to the identification of MMP polymorphisms and mutations causally implicated in the development of different genetic diseases. These genomic analyses have been further extended through the generation of animal models of gain- or loss-of-function for MMPs which have allowed the identification of novel functions for these enzymes and the establishment of causal relationships between MMP dysregulation and development of different human diseases. Further genomic studies of MMPs, including functional analysis of gene regulation and generation of novel animal models will help to answer the multiple questions still open in relation to a family of enzymes which strongly influence multiple events in life and disease.
基质金属蛋白酶（MMPs）是一个锌内肽酶大家族，在多种生理和病理过程中发挥重要作用。这些酶广泛分布于所有生物界，可能由一个单结构域蛋白进化而来，该蛋白经历了连续的复制、基因融合和外显子重排事件，从而产生了MMPs目前所展现的多结构域结构和功能多样性。为防止这些酶在包括癌症、关节炎和心血管疾病在内的多种疾病中产生不良活性，需要对其进行适当调控。多种激素、细胞因子和生长因子能够诱导MMP表达，尽管不同家族成员的组织特异性主要通过不同转录控制机制的组合来实现。多种信号通路的整合，再加上在MMP启动子处发现的几个顺式调控元件之间的协同作用，有助于对MMP转录活性进行严格的时空控制。此外，表观遗传机制，如DNA甲基化或组蛋白乙酰化，也可能有助于MMP的调控。同样，包括mRNA稳定性、蛋白质翻译效率和基于微小RNA的机制在内的转录后调控过程，最近也被描述为MMP基因表达的调节因子。平行研究已导致鉴定出与不同遗传疾病发生有因果关系的MMP多态性和突变。通过生成MMP功能获得或功能丧失的动物模型，这些基因组分析得到了进一步扩展，这使得能够确定这些酶的新功能，并建立MMP失调与不同人类疾病发生之间的因果关系。对MMPs的进一步基因组研究，包括基因调控的功能分析和新型动物模型的生成，将有助于回答与这一强烈影响生命和疾病中多个事件的酶家族相关的多个仍未解决的问题。
