Document Detail

Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells.
MedLine Citation:
PMID:  8633088     Owner:  NLM     Status:  MEDLINE    
Benzodiazepine (BZA)-5B, a CAAX farnesyl-transferase inhibitor, was previously shown to block the farnesylation of H-Ras and to reverse the transformed morphology of Rat1 cells expressing oncogenic H-RasV12. Non-transformed Rat1 cells were not affected by BZA-5B, suggesting that they produce a form of Ras whose prenylation is not blocked by this compound. The likely candidate is K-RasB, which differs from H-Ras primarily in the terminal 24 amino acids. In the current study we examined the effect of BZA-5B on the prenylation of a chimeric oncogenic Ras protein designated H/K-RasBV12, consisting of the first 164 amino acids of H-RasV12 followed by the last 24 amino acids of K-RasB. BZA-5B failed to block the prenylation of this chimera and was thus unable to reverse the transformed morphology of Rat1 cells in which it was expressed. Another potent inhibitor of H-Ras farnesylation, L-739,749, also failed to block prenylation of H/K-RasBV12. Similar results were obtained in transfected cells expressing a widely used version of K-RasBV12 containing a 10-amino acid extension at its NH2 terminus. Neither BZA-5B nor L-739,749 reversed the transformed morphology of cells expressing H/K-RasBV12. The resistance of K-RasB to farnesyltransferase inhibition provides a likely explanation for the resistance of nontransformed cells to the growth inhibitory effects of BZA-5B and L-739,749.
G James; J L Goldstein; M S Brown
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  93     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1996 Apr 
Date Detail:
Created Date:  1996-07-01     Completed Date:  1996-07-01     Revised Date:  2014-06-27    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4454-8     Citation Subset:  IM    
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MeSH Terms
Alkyl and Aryl Transferases*
Benzodiazepines / pharmacology*
Cell Line
Cell Transformation, Neoplastic / drug effects*
Enzyme Inhibitors / pharmacology*
Mevalonic Acid / pharmacology
Oligopeptides / pharmacology*
Protein Prenylation
Recombinant Fusion Proteins / biosynthesis,  metabolism
Transferases / antagonists & inhibitors*
ras Proteins / biosynthesis,  metabolism*
Grant Support
Reg. No./Substance:
0/BZA 5B; 0/Enzyme Inhibitors; 0/Oligopeptides; 0/Recombinant Fusion Proteins; 12794-10-4/Benzodiazepines; 156511-34-1/L 739749; EC 2.-/Transferases; EC 2.5.-/Alkyl and Aryl Transferases; EC; EC Proteins; S5UOB36OCZ/Mevalonic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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