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(Received for publication, March 12, 1997, and in revised form, April 25, 1997)
From the Protein farnesyltransferase inhibitors (FTIs)
inhibit Ras transformation and Ras-dependent tumor cell
growth, but the biological mechanisms underlying these activities is
unclear. In previous work, we presented support for the hypothesis that
the anti-transforming effects of FTIs depend upon alterations in the
function of RhoB, a member of the Rho family of proteins that regulate
cytoskeletal actin, cell adhesion, and cell growth. A significant
question that needed to be addressed was whether FTIs could directly
alter the prenylation as well as the function of RhoB in cells. This issue is complex because farnesylated and geranylgeranylated forms of
RhoB (RhoB-F and RhoB-GG) both exist in cells. Here, we show that RhoB
farnesylation in vitro can be catalyzed by protein
farnesyltransferase and that the peptidomimetic FTI
L-739,749 inhibits the farnesylation of RhoB both in
vitro and in intact cells. In drug-treated cells, the level of
RhoB-GG increased in parallel with the decrease in RhoB-F. In addition
to altering RhoB prenylation, L-739,749 suppressed RhoB-dependent cell growth. Taken together, the results
suggest that the inhibitory effects of FTIs on RhoB function can be
mediated by a relative loss of RhoB-F, a gain of RhoB-GG, or both. Our findings strengthen the causal link between RhoB inhibition and the
anti-transforming effects of FTIs and indicate that differently prenylated forms of RhoB may have unique functions.
Volume 272, Number 25,
Issue of June 20, 1997
pp. 15591-15594
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
§
,
,§
and
Wistar Institute, Philadelphia, Pennsylvania
19104, the § Cell and Molecular Biology Graduate Group,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104, and the 
Departments of Molecular Cancer
Biology and Biochemistry, Duke University Medical Center,
Durham, North Carolina 27710
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P. D. Emanuel, R. C. Snyder, T. Wiley, B. Gopurala, and R. P. Castleberry Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors Blood, January 15, 2000; 95(2): 639 - 645. [Abstract] [Full Text] [PDF]
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W. Du and G. C. Prendergast Geranylgeranylated RhoB Mediates Suppression of Human Tumor Cell Growth by Farnesyltransferase Inhibitors Cancer Res., November 1, 1999; 59(21): 5492 - 5496. [Abstract] [Full Text] [PDF]
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N. Mahgoub, B. R. Taylor, M. Gratiot, N. E. Kohl, J. B. Gibbs, T. Jacks, and K. M. Shannon In Vitro and In Vivo Effects of a Farnesyltransferase Inhibitor on Nf1-Deficient Hematopoietic Cells Blood, October 1, 1999; 94(7): 2469 - 2476. [Abstract] [Full Text] [PDF]
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W. Du, P. F. Lebowitz, and G. C. Prendergast Cell Growth Inhibition by Farnesyltransferase Inhibitors Is Mediated by Gain of Geranylgeranylated RhoB Mol. Cell. Biol., March 1, 1999; 19(3): 1831 - 1840. [Abstract] [Full Text] [PDF]
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N. Suzuki, K. Del Villar, and F. Tamanoi Farnesyltransferase inhibitors induce dramatic morphological changes of KNRK cells that are blocked by microtubule interfering agents PNAS, September 1, 1998; 95(18): 10499 - 10504. [Abstract] [Full Text] [PDF]
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P. F. Lebowitz, W. Du, and G. C. Prendergast Prenylation of RhoB Is Required for Its Cell Transforming Function but Not Its Ability to Activate Serum Response Element-dependent Transcription J. Biol. Chem., June 27, 1997; 272(26): 16093 - 16095. [Abstract] [Full Text] [PDF]
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Z. Chen, J. Sun, A. Pradines, G. Favre, J. Adnane, and S. M. Sebti Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice J. Biol. Chem., June 9, 2000; 275(24): 17974 - 17978. [Abstract] [Full Text] [PDF]
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C. Allal, G. Favre, B. Couderc, S. Salicio, S. Sixou, A. D. Hamilton, S. M. Sebti, I. Lajoie-Mazenc, and A. Pradines RhoA Prenylation Is Required for Promotion of Cell Growth and Transformation and Cytoskeleton Organization but Not for Induction of Serum Response Element Transcription J. Biol. Chem., September 29, 2000; 275(40): 31001 - 31008. [Abstract] [Full Text] [PDF]
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