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(Received for publication, April 3, 1997, and in revised form, June 13, 1997)
From the Burnham Institute, La Jolla, California 92037
Multiple tissue-specific, DNase-hypersensitive
sites are correlated with known or potential regulatory regions of the
human keratin 18 (K18) gene. One of these sites is found within exon 6, close to a potential AP-1 binding site. Footprint analysis confirmed
that this site is capable of binding c-Jun and c-Fos in
vitro. However, exon 6 can stimulate expression of a reporter gene driven by the K18 proximal promoter independent of AP-1 in F9
cells and additionally modulates AP-1 responsiveness when in combination with an intron enhancer. Analysis in transgenic mice and by
transient transfections of mutant forms of the K18 gene showed that
exon 6 contributes to the expression of the K18 gene. However,
substitution of part of exon 6 with the corresponding part of the
keratin 19 gene which lacks an AP-1 site decreased but did not destroy
the regulatory activity of the exon. Furthermore, this mutation did not
alter either the tissue specificity or the position-independent and
copy number-dependent behavior of the K18 gene. In
contrast, a frameshift mutation within exon 6 dramatically decreased
the expression of the gene. K18 RNA expression from the frameshift
mutation was less than 10% of the wild type K18 transgene. This
decline in expression was the result of a combination of decreased
stability of mutant K18 RNA and the creation of a negative regulatory
element that can interact with the first intron regulatory elements and
actively suppress K18 expression. These results demonstrate that a
protein-coding portion of the K18 gene also has a regulatory
function.
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