Transcriptional control of high molecular weight keratin gene expression in multistage mouse skin carcinogenesis.
Monospecific antikeratin antisera and specific complementary DNA probes were used to analyze expression of keratin genes in newborn mouse skin and skin papillomas and carcinomas by indirect immunofluorescence, immunoblotting, and in situ hybridization. Tumors were induced by initiation with 7,12-dimethylbenz[a]anthracene and promotion with 12-O-tetradecanoylphorbol-13-acetate. Type I epidermal keratin K14 protein (Mr 55,000) is found in all living layers of the newborn skin but is most abundant in the lower strata. K1 (Mr 67,000) and K10 (Mr 59,000) proteins are predominantly suprabasal and K1 is processed in the stratum corneum. Transcripts for K14 were confined largely to the basal cell layer by in situ hybridization. Transcripts for K1 and K10 were highly expressed in suprabasal cells including the granular cell layer. In benign tumors, distribution of K14 protein is similar to that in newborn skin, while the abundance of K1 and K10 appears to be somewhat reduced although the tissue distribution remains suprabasal. Transcription of K14 is aberrant in benign tumors and transcripts persist throughout much of the suprabasal cell layers. Transcripts of K1 and K10 are normally distributed in papillomas but grain density is less intense than in newborn epidermis. Keratin expression in carcinomas is highly disturbed. K14 protein and transcripts are highly expressed in all strata in carcinomas while protein and transcripts for K1 and K10 are essentially absent. These results suggest that papilloma cells fail to respond to or generate signals to regulate K14 expression in the differentiating suprabasal cell layers and may not fully express their suprabasal cell keratins. Carcinomas fail to express suprabasal cell keratins and this is regulated at the transcriptional level. The loss of suprabasal keratin expression may provide a marker for malignant conversion in the mouse skin carcinogenesis model.
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000831:Animals, Newborn; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D005260:Female; D005786:Gene Expression Regulation; D005796:Genes; D007633:Keratins / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D009693:Nucleic Acid Hybridization; D010212:Papilloma / Q000235:genetics / Q000473:pathology*; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate; D014158:Transcription, Genetic
D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D013755:Tetradecanoylphorbol Acetate