v-K-ras leads to preferential farnesylation of p21(ras) in FRTL-5 cells: multiple interference with the isoprenoid pathway.
The isoprenoid pathway in FRTL-5 thyroid cells was found to be deeply altered on transformation with v-K-ras. A dramatic overall reduction of protein prenylation was found in v-K-ras-transformed cells in comparison with the parent FRTL-5 cells, as shown by labeling cells with [3H]mevalonic acid. This phenomenon was accompanied by a relative increase of p21(ras) farnesylation and by a decrease of the ratio between the amounts of geranylgeraniol and farnesol bound to prenylated proteins. Analysis of protein prenylation in FRTL-5 cells transformed by a temperature-sensitive mutant of the v-K-ras oncogene indicated that these variations represent an early and specific marker of active K-ras. Conversely, FRTL-5 cells transformed with Harvey-ras showed a pattern of [3H]-mevalonate (MVA)-labeled proteins similar to that of nontransformed cells. The K-ras oncogene activation also resulted in an overall decrease of [3H]-MVA incorporation into isopentenyl-tRNA together with an increase of unprocessed [3H]-MVA and no alteration in [3H]-MVA uptake. The effects of v-K-ras on protein prenylation could be mimicked in FRTL-5 cells by lowering the concentration of exogenous [3H]-MVA whereas increasing the [3H]-MVA concentration did not revert the alterations observed in transformed cells. Accordingly, v-K-ras expression was found to: (i) down-regulate mevalonate kinase; (ii) induce farnesyl-pyrophosphate synthase expression; and (iii) augment protein farnesyltransferase but not protein geranylgeranyl-transferase-I activity. Among these events, mevalonate kinase down-regulation appeared to be related strictly to differential protein prenylation. This study represents an example of how expression of the v-K-ras oncogene, through multiple interferences with the isoprenoid metabolic pathway, may result in the preferential farnesylation of the ras oncogene product p21(ras).
Laezza
C
C
Centro di Endocrinologia ed Oncologia-Sperimentale "G. Salvatore"/Consiglio Nazionale delle Ricerche (Italy).
Di Marzo
V
V
Bifulco
M
M
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D005204:Farnesol / Q000378:metabolism*; D051231:Farnesyltranstransferase; D011905:Genes, ras; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology
D005204:Farnesol; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D015689:Oncogene Protein p21(ras)