Alterations in epidermal biochemistry as a consequence of stage-specific genetic changes in skin carcinogenesis.
The induction of cancer on mouse skin by initiation-promotion protocols occurs through stages in which a benign squamous papilloma is an obligate precursor of squamous cell carcinoma. Activation of the Ha-ras gene is sufficient to produce the papilloma phenotype, while additional genetic changes are required for malignant conversion. The introduction of Ha-ras into normal keratinocytes suppresses the expression of differentiation markers, keratin K1 and K10, and loricrin (a cornified envelope precursor) and, to a lesser extent, filaggrin, at the level of transcription. However, cells initiated by Ha-ras express a nonepidermal keratin, K8. The transcription of K8 in these cells is sensitive to the level of medium Ca2+, being abundant in 0.5 mM Ca2+ and not detected in 0.05 mM Ca2+. Epidermal differentiation is regulated by signalling, which involves changes in phosphatidylinositol turnover and intracellular Ca2+. Cells initiated by Ha-ras do not differ from normal keratinocytes in their intracellular Ca2+ response patterns, at least in response to changes in extracellular Ca2+ and serum factors. However, c-Ha-ra keratinocytes have a high basal level of phosphatidylinositol (PI) turnover, which is additive with several other inducers of this pathway, including Ca2+ and aluminum fluoride. Additional studies suggest that high turnover of the PI pathway is incompatible with differentiation-specific gene expression in keratinocytes. We suggest this negative relationship is mediated through elevated diacylglycerol production and chronic down-modulation of protein kinase C. Protein kinase C is known to be essential for expression of differentiation-related genes in keratinocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Yuspa
S H
SH
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, MD 20892.
Kilkenny
A
A
Cheng
C
C
Roop
D
D
Hennings
H
H
Kruszewski
F
F
Lee
E
E
Strickland
J
J
Greenhalgh
D A
DA
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D002478:Cells, Cultured; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D016761:Oncogene Proteins v-fos / Q000235:genetics* / Q000502:physiology; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012190:Retroviridae; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D014162:Transfection
D014408:Biomarkers, Tumor; D002273:Carcinogens; D016761:Oncogene Proteins v-fos; D015689:Oncogene Protein p21(ras); D002118:Calcium