Abstract
Here we demonstrate that the geranylgeranyltransferase-I inhibitor GGTI-298 inhibits the RhoB pathway and disrupts stress fiber and focal adhesion formation in NIH-3T3 cells. Farnesylated (V14)RhoB-CAIM (resistant to GGTI-298), but not geranylgeranylated (V14)RhoB (-CLLL), prevented inhibition of actin stress fiber and focal adhesion formation, underlining the critical role of RhoB. In contrast, farnesylated, (V14)RhoA (-CVLS) was unable to prevent effects of GGTI 298 on cytoskeleton organization. Furthermore, the ability of GGTI-298 to induce p21(WAF) and to block cells in the G(0)/G(1) phase of the cell cycle was also prevented by farnesylated (V14)RhoB but not by farnesylated (V14)RhoA. Moreover, treatment with GGTI-298 of cells expressing farnesylated RhoB results in accumulation of these cells in the G(2)/M phase. Therefore, the RhoB pathway is a critical target of GGTI-298.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / enzymology*
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / metabolism
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Animals
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Benzamides / pharmacology
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Cell Cycle / drug effects
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Cell Cycle / physiology
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Cell Cycle Proteins / drug effects
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Cell Cycle Proteins / metabolism*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / drug effects
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Cyclins / metabolism
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Enzyme Inhibitors / pharmacology
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Eukaryotic Cells / drug effects
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Eukaryotic Cells / enzymology*
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Focal Adhesions / drug effects
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Focal Adhesions / enzymology
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Intracellular Signaling Peptides and Proteins
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Mice
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Protein Prenylation / physiology*
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Recombinant Fusion Proteins
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Stress Fibers / drug effects
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Stress Fibers / metabolism
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rho-Associated Kinases
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rhoA GTP-Binding Protein / drug effects
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rhoA GTP-Binding Protein / metabolism
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rhoB GTP-Binding Protein / drug effects
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rhoB GTP-Binding Protein / metabolism*
Substances
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Benzamides
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Cdkn1a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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GGTI 298
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Intracellular Signaling Peptides and Proteins
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Recombinant Fusion Proteins
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Alkyl and Aryl Transferases
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geranylgeranyltransferase type-I
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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rhoA GTP-Binding Protein
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rhoB GTP-Binding Protein