We have previously described the three loci CK‐CA, CK‐CB and CK‐CC in the human genome that contain clustered type‐I cytokeratin genes and reported the complete nucleic acid sequences of the functional cytokeratin 17 gene located in CK‐CA and two closely related pseudogenes present in CK‐CB and CK‐CC [Troyanovsky, S. M., Leube, R. E. & Franke, W. W. (1992) Eur. J. Cell Biol. 59, 127–137]. By nucleic acid sequence analysis, we now show that extensive similarities between the functional gene and the pseudogenes exist in the 5′‐upstream region. However, despite the high degree of nucleic acid identity (94%), only the 5′‐upstream region of the functional gene was able to induce significant transcriptional activity in transfected cells of epithelial origin. Using chimeric upstream regions consisting of different fragments from the pseudogene and the functional gene, we made the surprising observation that cis elements in the proximal 5′‐upstream region of the pseudogene promoter can cooperate with distal enhancer elements of the functional gene to induce strong chloramphenicol‐O ‐acetyltransferase activity in transfected HeLa cells. A major site in the proximal upstream region was identified by deoxyribonuclease protection experiments to be necessary for this cooperative effect. The structure and properties of this element were further analysed by transfection of different chloramphenicol‐O ‐acetyltransferase gene constructs, and by nucleic acid sequence comparison to corresponding regions of the related cytokeratins 14 and 16. It is concluded that the upstream regions identified in this study contribute to the strong expression of the human cytokeratin 17 gene in a coordinated fashion.
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