EFFECTS OF THE FARNESYLTRANSFERASE INHIBITOR UCF-1C MANUMYCIN ON GROWTH AND P21-RAS POSTTRANSLATIONAL PROCESSING IN NIH3T3 CELLS/

Examination of the effect of the farnesylprotein transferase (FPTase) inhibitor UCFI-C/manumycin on NIH3T3 cells transfected with a normal N -ras gene and expressing high levels of the corresponding p21-ras prot ein showed that IO mu m UCFI-C immediately and reversibly inhibited gr owth in these cells, without modifying cell-death rate, thus acting as a cytostatic, There was also a 98% reduction of p21-ras neo-farnesyla tion and a 3-fold decrease in total content in p21-ras products, yet w ithout gross modification of the relative content in the post-translat ional products and without accumulation of the native protein to detec table levels. UCFI-C likewise reversibly inhibited growth in parental NIH3T3 cells, as well as in sub-strains expressing a transfected norma l or mutated H-ras gene. Together with the fact that the well-develope d network of actin stress fibers present in the NIH3T3 (N-ras) cells w as not affected by the FPTase inhibitor, these data indicate that its growth-inhibitory effect is not necessarily in direct relation with th at exerted on p21-ras processing. Alternatively, it might be causally related to the decreased prenylation of other cellular proteins, perha ps included among the 13 proteins, unrelated to p21-ras, of which the farnesylation was also reduced under UCFI-C treatment. Some cells tran sformed by a ras or non-ras oncogene might exhibit higher susceptibili ty towards FPTase inhibitors than normal cells, but this might then be attributable to differences in the pattern of expression and/or in th e functional importance of non-ras farnesylated proteins. (C) 1998 Wil ey-Liss, Inc.