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 farnesyltrans ferase activity in mammalian tumors and its relationship to the proces sing of cytosolic p21 that leads to tumorigenesis are unknown. We repo rt 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 epider mal in origin, and kinetic studies with cytosol from epidermis and pap illomas showed that the reaction was linear with respect to time, subs trate concentration, and protein content. Skin papillomas showed signi ficantly elevated levels of both cytosolic and membrane-bound Ha-ras p 21,whereas far lesser cytosolic and almost negligible amounts of membr ane-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. (C) 1993 Wiley-Liss, Inc.