AI Article Synopsis
- The 5-lipoxygenase (5LO) enzyme is crucial for producing leukotrienes, which are linked to various inflammatory diseases like atherosclerosis.
- The study explored how multiple GC-boxes in the 5LO gene promoter affect its expression in human monocytic cells (MM6), finding that a compound called mithramycin reduces this expression, indicating the importance of GC-rich sequences.
- A novel Sp1 binding site was discovered near the transcription start point, and mutations in this site decreased Sp1 binding and reporter gene expression, suggesting its role as a key element for the basic transcription of the 5LO gene, rather than being affected by differentiation signals.
Article Abstract
5-lipoxygenase (5LO) catalyzes formation of leukotrienes, mediators with roles in several inflammatory disorders, including atherosclerosis. The human 5LO gene promoter contain multiple GC-boxes. The relevance of these for expression of 5LO in the human monocytic cell line Mono Mac 6 (MM6) was studied. A downregulating effect of the GC-box binding compound mithramycin indicated that GC-rich sequences in the 5LO gene promoter are important for expression of native 5LO. In DNase I footprinting, mithramycin and Sp1 protected known GC-boxes, but also a novel Sp1 binding site was found, comprising 20 bp upstream of the major transcription initiation site, beside an Initiator-like sequence. Mutation of this site reduced Sp1 binding and expression of reporter genes in MM6 cells, compatible with a function as basal promoter element for the TATA-less 5LO gene. When differentiation was induced by TGFbeta and vitamin D(3), 5LO expression became prominent, but expression levels of Sp1/3 and Egr-1 were the same as for control cells. Also, 5LO reporter gene activity in transiently transfected MM6 cells was insensitive to differentiation. Thus, the GC-rich part of the 5LO gene promoter, including a novel Sp1 site, appear important for basal (rather than upregulated) transcription of 5LO in MM6 cells.
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| http://dx.doi.org/10.1016/j.bbalip.2005.11.008 | DOI Listing |
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