Farnesylated RhoB prevents cell cycle arrest and actin cytoskeleton disruption caused by the geranylgeranyltransferase I inhibitor GGTI-298.
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.
Allal
Cuider
C
Département Innovation Thérapeutic et Oncologie Moléculaire, Centre de Physiopathologie Toulous Purpan, INSERM U563, Institut Claudius Regaud, France.
Pradines
Anne
A
Hamilton
Andrew D
AD
Sebti
Said M
SM
Favre
Gilles
G
D016475:3T3 Cells; D008841:Actin Cytoskeleton / Q000187:drug effects / Q000201:enzymology*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005057:Eukaryotic Cells / Q000187:drug effects / Q000201:enzymology*; D022001:Focal Adhesions / Q000187:drug effects / Q000201:enzymology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D017368:Protein Prenylation / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism*
D001549:Benzamides; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; C102521:GGTI 298; D047908:Intracellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D020743:rhoB GTP-Binding Protein