The tissue-dependent keratin 19 gene transcription is regulated by GKLF/KLF4 and Sp1.
Keratins play critical roles in cellular differentiation and cytoskeletal organization. Keratin 19 (K19) is unique because it has been implicated as a marker of stem cells in some tissues, such as the hair follicle in the skin. It is also associated with malignant transformation in esophageal and pancreatic cancers. Here, we show that the K19 promoter is active in a subset of gastrointestinal cancer cells derived from esophageal and pancreas but inactive in other contexts. This activity was mapped to a short region containing an overlapping binding site for gut-enriched Krüppel-like factor (GKLF/KLF4) and Sp1. GKLF has a higher binding affinity and is the predominant binding factor in cells with low Sp-1 protein levels. Pancreatic acinar cells normally do not express K19, but overexpression of GKLF and Sp1 in these cells leads to aberrant expression, similar to what is observed in pancreatic cancer. These results demonstrate the functional interaction of ubiquitous and tissue-restricted transcription factors in determining tissue- and neoplasm-specific patterns of gene expression.
Brembeck
F H
FH
Gastroenterology Division, Cancer Center, and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Rustgi
A K
AK
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007633:Keratins / Q000235:genetics*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051381:Rats; D016415:Sequence Alignment; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016335:Zinc Fingers
D017931:DNA Primers; D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D007633:Keratins