Genes coding MMPs were localized on chromosomes 11, 14, 16, 20, and 22. Genes coding several secreted, soluble proteases form clusters. For instance, the long arm of chromosome 11 harbors sequentially (oriented from the most centromeric to the most telomeric regions) genes coding for MMP-8, MMP-10, MMP-1, MMP-12, MMP-7, and MMP-13. In contrast, the genes coding for membrane-type MMPs were localized on different chromosomes; MMP14 (MT1-MMP) maps to human chromosome 14, MMP15 (MT-2-MMP) to human chromosome 16, and MMP16 (MT-3-MMP) to human chromosome 8.
A paradigm of MMP gene structure and organization is the MMP-12 (human macrophage elastase) gene. It is similar to the genes of stromelysins and collagenases because it has the same location to chromosome 11q22.2-22.3 and similar, highly conserved exon size and intron-exon borders. It is 13-kilobase (kb) long, composed of 10 exons and
9 introns. It was determined that MMP-12 (macrophage elastase) and MMP-3 (stromelysin 1) genes are physically linked within the 62-kb region. The promoter region of the MMP-12 gene contains several features common to other MMP genes, including a TATA box 29 nucleotides upstream to the transcription initiation site, an AP-1 motif located about -70kb upstream, and a PEA3 element. The PEA3 is a conserved Polyoma Enhancer A binding protein site, and the AP-1 is an Activation Protein 1 binding element. Both are regions of DNA that bind directly to these transcription factors. Other regulatory elements within different MMP genes include GC-Sp-1 binding site, SBE-SIAT binding element, c/EBP-b-CCATT/enhancer binding protein b, OSE-2 (osteoblast specific element-2), SPRE (stromelysin-1 PDGF responsive element), TRE (octamer binding protein), Sil (silencer sequence), NF-kb (nuclear factor kb), NF-1 (nuclear factor-1), and RARE (retinoic acid responsive element). Some of these sites overlap. For instance, the phor-bol ester-responsive element is located within the AP-1 binding region.
Under normal conditions, the level of MMPs is rather low and increases with the need for ECM remodeling. Thus, the MMP genes are susceptible to external induction, which occurs with participation of the regulatory elements listed above. Regulation at the translational level may occur via modulation of mRNA or via second messenger signaling.
The agents affecting gene expression are inflammatory cytokines, growth factors, hormones, phorbol esters, oxidant stress, and mechanical injury or aging. They act through the whole variety of intracellular signaling pathways, including mitogen-activated protein kinases. These pathways may cross-react with each other, resulting in a broad spectrum of intermediating proteins (enhancers, co-regulators, or inhibitors) that in turn form complexes with transcription factors. These complexes eventually bind to AP-1 or other regulatory elements in the promoter region of the MMP gene.
A good example of the level of complexity is transforming growth factor (TGF)-p. TGF-b is a potent regulator of many genes that carry AP-1 motifs in their promoters. It generally induces expression of MMP inhibitors (TIMPs) and expression of genes coding for ECM proteins that are substrates for MMPs, but suppresses synthesis of MMPs 1, 3, and 9. For its suppressive activity, TGF-b binds to its transmembrane receptor and activates the cascade of phosphorylation of Smad family proteins. These proteins can then be translocated to the nucleus, where they bind to a TGF-b inhibitory element (TIE). This is a sequence: 5'-GAATTGGAGA-3', located 245 bp upstream of the transcription site and upstream of the AP-1 site in the MMP-1 promoter. TIE is considered to be a constitutive repressor of the MMPs. In carcinoma cells, TGF-b has an opposite effect, in that by acting through a protein kinase C and tyro-sine kinase signaling pathways, it enhances expression and synthesis of MMP-13 [7, 8].
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