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J Biol Chem, Vol. 273, Issue 32, 20243-20251, August 7, 1998
From the Program in Cell Biology and Department of Medicine,
Memorial Sloan-Kettering Cancer Center,
New York, New York 10021
Farnesylation is required for the membrane
partition and function of several proteins, including Ras.
Farnesyl-protein transferase inhibitors (FTIs) were developed to
prevent Ras processing and thus to be effective agents for the
treatment of cancers harboring mutated ras. However, FTIs
inhibit the growth of most tumor cells and several xenograft models,
irrespective of whether they possess mutated ras.
Furthermore, the antiproliferative effect is not correlated with
inhibition of Ki-Ras processing; tumors with wild type ras
are inhibited, and FTIs are not particularly toxic. These data suggest
that the mechanism of FTI action is complex and may involve other
targets besides Ras. To begin to understand how FTIs work, we
investigated the mechanism of growth inhibition. FTI causes
G1 arrest in a subset of sensitive lines. This is
accomplished by transcriptional induction of p21, which mediates the
inhibition of cyclin E-associated protein kinase activity, pRb
hypophosphorylation and inhibition of DNA replication. Induction of p21
is p53-dependent; it does not occur in cells with mutant
p53 or in cells expressing human papillomavirus E6. However, neither
p53 nor p21 are required for inhibition of cell proliferation. FTI
still blocks the growth of cells deficient in these proteins. In the
absence of p21, G1 block is relaxed, DNA replication is not
affected, and cells become polyploid and undergo apoptosis. These
results suggest that farnesylated protein(s) may be involved in
regulating p53 function and in coordinating entrance into S, and that
the consequences of FTI treatment are a function of the other mutations
found in the tumor cell.
A Farnesyl-Protein Transferase Inhibitor Induces p21
Expression and G1 Block in p53 Wild Type Tumor Cells
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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