Transcriptional regulation of MMPs

Increased MMP expression in tumors is primarily associated with transcriptional changes rather than genetic alterations, although translocation of MMP23 genes in neuroblastoma and amplification of MMP24 gene have been reported (Llano, 1999). Transcriptional regulation of MMP mRNA expression is subject to influences by several chemical reagents, neurohormones, and cytokines (Liotta et al., 1983; Unemori and Werb, 1988; Galis et al., 1994; Werb et al., 1989; Matrisian and Hogan, 1990). For example, tumor necrosis factor alpha (TNF-a) and interleukin-1 can stimulate the production of MMP-1, MMP-3, and MMP-9 (MacNaul et al., 1990). While the pathways by which these factors regulate MMP transcription remain to be determined, it is known that the MMP promoter regions contain response elements that transcriptionally regulate expression. Tumor response element (TRE) and activation protein-1 (AP-1) binding sites are present in MMP-1, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12 and MMP-13 (Benbow and Brinkerhoff, 1997). Transcriptional regulation can be further influenced either by genetic polymorphisms or by growth factor-activated transcription factors. MMP-1 protein expression is influenced by polymorphisms in MMP-1 gene promoter. Promoters of inducible MMPs and TIMPs have specific sites that bind AP-1 and Polyoma Enhancer A-binding Protein-3 (PEA-3), which is pivotal in transcriptional activation. While Fos and Jun families of transcription factors bind to AP-1 sites, PEA-3 binds to the Ets binding sites (EBS). The presence of two guanine nucleotides in the MMP-1 promoter creates a functional Ets-binding site adjacent to an AP-1 site, up-regulating the transcription of MMP-1 gene in multiple cancers, including ovarian cancers (Kanamori, 1999). MMP transcription can also be downregulated in response to certain signals. For example, MMP-1 transcription can be repressed in the presence of the tumor suppressor p53 (Sun et al., 1999). Interestingly, p53 is also known to differentially regulate MMP-13 expression (Sun et al., 2000). Another example of transcriptional regulation of MMPs is the up-regulation of MMP-7 expression in colon tumors (Crawford, 2001). The PEA-3 subfamily of Ets transcription factors and the p-catenin-LEF-1 complex activate MMP-7 expression in colon tumors. These findings suggest that multiple regulatory elements in MMP promoter regions coor-dinately regulate tissue-specific and temporal expression of MMP.

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