JBC Origene Your Gene Company

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Law, B. K.
Right arrow Articles by Moses, H. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Law, B. K.
Right arrow Articles by Moses, H. L.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

J Biol Chem, Vol. 275, Issue 15, 10796-10801, April 14, 2000

Farnesyltransferase Inhibitor Induces Rapid Growth Arrest and Blocks p70s6k Activation by Multiple Stimuli*

Brian K. LawDagger §, Peter Nørgaard||, and Harold L. MosesDagger §**

From the Dagger  Vanderbilt Ingram Cancer Center and the § Department of Cell Biology Vanderbilt University, Nashville, Tennessee 37232 and the || Institute of Pathological Anatomy, Glostrup University Hospital, DK-2600 Glostrup, Denmark

We have previously shown that the peptidomimetic farnesyltransferase inhibitor L-744,832 (FTI) inhibits p70s6k activation and cell growth in a mouse keratinocyte cell line but only at concentrations of FTI significantly higher than those required for the inhibition of Ras farnesylation. Here we show that the rapid kinetics of FTI inhibition of DNA synthesis (within 1.5 h) in both normal and v-K-Ras transformed keratinocytes matches the rapid kinetics of p70s6k inhibition observed previously. It is further shown that FTI inhibits p70s6k activation in response to serum, phorbol myristate acetate, and increased amino acid levels. The phosphatase inhibitor calyculin A partially reverses the FTI-induced dephosphorylation of p70s6k, suggesting that FTI may act upstream of a protein phosphatase. A rapamycin-resistant mutant of p70s6k is shown to be resistant to FTI-induced dephosphorylation of the major rapamycin-sensitive phosphorylation site of p70s6k, Thr389. Together, these data demonstrate that FTI rapidly inhibits DNA synthesis irrespective of the presence of v-K-Ras and that FTI inhibits p70s6k activation in response to multiple stimuli. Because the FTI L-744,832 mimics many of the effects of rapamycin, this FTI may prove effective against tumors that exhibit inappropriate activation of the mTOR/p70s6k pathway.

* This work was supported by National Institutes of Health Grant CA-42572 (to H. L. M.) and the Frances Williams Preston Laboratories of the T. J. Martell Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by an American Association for Cancer Research-Amgen, Inc. Fellowship in Translational Research.

** To whom correspondence should be addressed: Vanderbilt Ingram Cancer Center, 649 Medical Research Bldg. II, Nashville, TN 37232-6838. Tel.: 615-936-1872; Fax: 615-936-1790; E-mail: hal.moses@mcmail.vanderbilt.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 BloodHome page
R. E. Marks, A. W. Ho, C. Robbel, T. Kuna, S. Berk, and T. F. Gajewski
Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level
Blood, September 15, 2007; 110(6): 1982 - 1988.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H.-C. Chang, C.-Y. Cho, and W.-C. Hung
Silencing of the Metastasis Suppressor RECK by RAS Oncogene Is Mediated by DNA Methyltransferase 3b-Induced Promoter Methylation.
Cancer Res., September 1, 2006; 66(17): 8413 - 8420.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
M. Law, E. Forrester, A. Chytil, P. Corsino, G. Green, B. Davis, T. Rowe, and B. Law
Rapamycin Disrupts Cyclin/Cyclin-Dependent Kinase/p21/Proliferating Cell Nuclear Antigen Complexes and Cyclin D1 Reverses Rapamycin Action by Stabilizing These Complexes
Cancer Res., January 15, 2006; 66(2): 1070 - 1080.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. D. Basso, A. Mirza, G. Liu, B. J. Long, W. R. Bishop, and P. Kirschmeier
The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) Inhibits Rheb Farnesylation and mTOR Signaling: ROLE IN FTI ENHANCEMENT OF TAXANE AND TAMOXIFEN ANTI-TUMOR ACTIVITY
J. Biol. Chem., September 2, 2005; 280(35): 31101 - 31108.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. Tabernero, F. Rojo, I. Marimon, M. Voi, J. Albanell, M. Guix, F. Vazquez, J. Carulla, M. Cooper, J. Andreu, et al.
Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors
J. Clin. Oncol., April 10, 2005; 23(11): 2521 - 2533.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
Y. Dai, M. Rahmani, X.-Y. Pei, P. Khanna, S. I. Han, C. Mitchell, P. Dent, and S. Grant
Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK
Blood, February 15, 2005; 105(4): 1706 - 1716.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
L. P. McMahon, W. Yue, R. J. Santen, and J. C. Lawrence Jr
Farnesylthiosalicylic Acid Inhibits Mammalian Target of Rapamycin (mTOR) Activity Both in Cells and in Vitro by Promoting Dissociation of the mTOR-Raptor Complex
Mol. Endocrinol., January 1, 2005; 19(1): 175 - 183.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Chytil, M. Waltner-Law, R. West, D. Friedman, M. Aakre, D. Barker, and B. Law
Construction of a Cyclin D1-Cdk2 Fusion Protein to Model the Biological Functions of Cyclin D1-Cdk2 Complexes
J. Biol. Chem., November 12, 2004; 279(46): 47688 - 47698.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
T. E. Harris and J. C. Lawrence Jr.
TOR Signaling
Sci. Signal., December 9, 2003; 2003(212): re15 - re15.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
P. H. Patel, N. Thapar, L. Guo, M. Martinez, J. Maris, C.-L. Gau, J. A. Lengyel, and F. Tamanoi
Drosophila Rheb GTPase is required for cell cycle progression and cell growth
J. Cell Sci., September 1, 2003; 116(17): 3601 - 3610.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. F. Castro, J. F. Rebhun, G. J. Clark, and L. A. Quilliam
Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner
J. Biol. Chem., August 29, 2003; 278(35): 32493 - 32496.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. C. Rose, F. Y. F. Lee, C. R. Fairchild, M. Lynch, T. Monticello, R. A. Kramer, and V. Manne
Preclinical Antitumor Activity of BMS-214662, a Highly Apoptotic and Novel Farnesyltransferase Inhibitor
Cancer Res., October 1, 2001; 61(20): 7507 - 7517.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
A. A. Adjei
Blocking Oncogenic Ras Signaling for Cancer Therapy
J Natl Cancer Inst, July 18, 2001; 93(14): 1062 - 1074.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. K. Law, M. E. Waltner-Law, A. J. Entingh, A. Chytil, M. E. Aakre, P. Norgaard, and H. L. Moses
Salicylate-induced Growth Arrest Is Associated with Inhibition of p70s6k and Down-regulation of c-Myc, Cyclin D1, Cyclin A, and Proliferating Cell Nuclear Antigen
J. Biol. Chem., December 1, 2000; 275(49): 38261 - 38267.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. M. Wright, A. L. Henneberry, T. A. Lagace, N. D. Ridgway, and C. R. McMaster
Uncoupling Farnesol-induced Apoptosis from Its Inhibition of Phosphatidylcholine Synthesis
J. Biol. Chem., June 29, 2001; 276(27): 25254 - 25261.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 All ASBMB Journals   Molecular and Cellular Proteomics 
 Journal of Lipid Research   ASBMB Today 
Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.