Expression of the carcinoma-associated keratin K6 and the role of AP-1 proto-oncoproteins.
The normal pattern of keratin expression in epidermis is altered in carcinomas as well as in nonmalignant diseases such as psoriasis and wound healing. Under these circumstances, the transcription of differentiation-specific keratins K1 and K10 is suppressed, whereas the activation- and hyperproliferation-associated keratins K6 and K16 are induced. Very little is known regarding transcriptional regulators involved in this switch. To investigate the nuclear factors that participate in regulation of expression of the K6 gene, we have characterized the binding sites for nuclear proteins on the promoter DNA of the K6 gene by gel retardation assays and site-specific deletion mutagenesis. We found four nuclear protein binding sites in the K6 gene promoter. Two are near the TATA box, but their ability to bind HeLa or keratinocyte nuclear extracts is independent of the TATA box-binding protein complex. The third binding site is a large palindrome. The sequences of these three sites do not correspond to any described target sequences for characterized transcriptional factors. The fourth is an AP-1 site, the target sequence for the proto-oncoproteins fos and jun. All four sites are independent of the previously characterized epidermal growth factor-responsive element, EGF-RE. These findings suggest that there may be two parallel pathways of induction of K6 transcription. One proceeds through the EGF-RE, which may be involved in nonmalignant hyperproliferation processes; the other, through the AP-1 site and the fos-jun proto-oncoproteins, may be related to induction in malignant processes.
Bernerd
F
F
Ronald O. Perelman Department of Dermatology, New York University Medical Center, NY 10016.
Magnaldo
T
T
Freedberg
I M
IM
Blumenberg
M
M
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D004273:DNA, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007633:Keratins / Q000378:metabolism*; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D016385:TATA Box; D014162:Transfection
D004273:DNA, Neoplasm; D016755:Proto-Oncogene Proteins c-jun; D007633:Keratins