ras protein p21 processing enzyme farnesyltransferase in chemical carcinogen-induced murine skin tumors.
Farnesylation of ras protein p21 is crucial for the protein's membrane localization, which is essential for its cell-transforming activity, which in turn is thought to be critical for the ultimate induction of cancer. The cytosolic enzyme farnesyltransferase plays a major role in posttranslational modification of p21, but the level of farnesyltransferase activity in mammalian tumors and its relationship to the processing of cytosolic p21 that leads to tumorigenesis are unknown. We report here that farnesyltransferase activity was significantly higher in chemical carcinogen-induced benign skin papillomas in SENCAR mice than in the epidermises of control animals. The enzyme is primarily epidermal in origin, and kinetic studies with cytosol from epidermis and papillomas showed that the reaction was linear with respect to time, substrate concentration, and protein content. Skin papillomas showed significantly elevated levels of both cytosolic and membrane-bound Ha-ras p21, whereas far lesser cytosolic and almost negligible amounts of membrane-bound p21 were present in the epidermis of control mice. There was a positive correlation between increased enzyme activity in papilloma cytosol and the processing of overexpressed cytosolic Ha-ras p21 for its localization to membrane.
Agarwal
R
R
Department of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106.
Khan
S G
SG
Athar
M
M
Zaidi
S I
SI
Bickers
D R
DR
Mukhtar
H
H
D019883:Alkyl and Aryl Transferases; D000595:Amino Acid Sequence; D000818:Animals; D002273:Carcinogens; D002462:Cell Membrane / Q000201:enzymology; D002855:Chromatography, Thin Layer; D003062:Codon / Q000235:genetics; D003600:Cytosol / Q000201:enzymology; D004817:Epidermis / Q000187:drug effects / Q000201:enzymology; D051231:Farnesyltranstransferase; D005260:Female; D011905:Genes, ras / Q000502:physiology; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010212:Papilloma / Q000139:chemically induced* / Q000201:enzymology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D014166:Transferases / Q000378:metabolism*
D002273:Carcinogens; D003062:Codon; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras)