L. Sepplorenzino et N. Rosen, A FARNESYL-PROTEIN TRANSFERASE INHIBITOR INDUCES P21 EXPRESSION AND G(1) BLOCK IN P53 WILD-TYPE TUMOR-CELLS, The Journal of biological chemistry, 273(32), 1998, pp. 20243-20251
Farnesylation is required for the membrane partition and function of s
everal proteins, including Ras. Farnesyl-protein transferase inhibitor
s (FTIs) were developed to prevent Ras processing and thus to be effec
tive agents for the treatment of cancers harboring mutated ras. Howeve
r, FTIs inhibit the growth of most tumor cells and several xenograft m
odels, irrespective of whether they possess mutated ras, Furthermore,
the antiproliferative effect is not correlated with inhibition of Ki-R
as processing; tumors with wild type ras are inhibited, and FTIs are n
ot particularly toxic. These data suggest that the mechanism of FTI ac
tion is complex and may involve other targets besides Ras, To begin to
understand how FTIs work, we investigated the mechanism of growth inh
ibition. FTI causes G(1) arrest in a subset of sensitive lines. This i
s accomplished by transcriptional induction of p21, which mediates the
inhibition of cyclin E-associated protein kinase activity, pRb hypoph
osphorylation and inhibition of DNA replication. Induction of p21 is p
53-dependent; it does not occur in cells with mutant p53 or in cells e
xpressing human papillomavirus E6, However, neither p53 nor p21 are re
quired for inhibition of cell proliferation. FTI still blocks the grow
th of cells deficient in these proteins. In the absence of p21, G(1) b
lock is relaxed, DNA replication is not affected, and cells become pol
yploid and undergo apoptosis. These results suggest that farnesylated
protein(s) may be involved in regulating p53 function and in coordinat
ing entrance into S, and that the consequences of FTI treatment are a
function of the other mutations found in the tumor cell.