Inhibition of DNA synthesis by a farnesyltransferase inhibitor involves inhibition of the p70(s6k) pathway.

Law BK, Nørgaard P, Gnudi L, Kahn BB, Poulson HS, Moses HL
J Biol Chem. 1999 274 (8): 4743-8

PMID: 9988711 · DOI:10.1074/jbc.274.8.4743

Previously, the protein farnesyltransferase inhibitor (FTI), L-744, 832, has been shown to inhibit the proliferation of a number of tumor cell lines in vitro in a manner that correlated with the inhibition of the mitogen-activated protein kinase cascade. Here we show that FTI inhibits p70(s6k) phosphorylation in mammary tumors in vivo in transgenic mice. Furthermore, in a mouse keratinocyte cell line, FTI inhibits p70(s6k) phosphorylation and activity and inhibits PHAS-1 phosphorylation in vitro in both rapidly growing cells and in growth factor-stimulated quiescent cells. Dominant-negative Ras expression inhibits p70(s6k) stimulation by epidermal growth factor, demonstrating a requirement for Ras activity during p70(s6k) activation. FTI does not inhibit protein kinase B phosphorylation on Ser473, indicating that FTI does not act by inhibiting phosphatidylinositol 3-kinase. FTI also inhibits DNA synthesis in keratinocytes, and inhibition of DNA synthesis correlates closely with p70(s6k) inhibition. Rapamycin, an inhibitor of p70(s6k) and PHAS-1 phosphorylation, causes a 30-45% reduction in DNA synthesis in keratinocytes, while FTI induces an 80-90% reduction in DNA synthesis. These observations suggest that alteration of p70(s6k) and PHAS-1 function by FTI are responsible for a substantial portion of the growth-inhibitory properties of FTI. Together, these data demonstrate that p70(s6k) and PHAS-1 are novel downstream targets of FTI and suggest that the anti-tumor properties of FTI are probably due to the inhibition of multiple mitogenic pathways.

MeSH Terms (22)

Adaptor Proteins, Signal Transducing Alkyl and Aryl Transferases Animals Carrier Proteins Cell Cycle Proteins Cell Division Cell Line DNA Replication Enzyme Inhibitors Eukaryotic Initiation Factors Farnesyltranstransferase Keratinocytes Methionine Mice Mice, Inbred BALB C Mice, Transgenic Phosphoproteins Phosphorylation ras Proteins Ribosomal Protein S6 Kinases Sirolimus Tumor Cells, Cultured

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