Protein geranylgeranylation, not farnesylation, is required for the G1 to S phase transition in mouse fibroblasts.
In order to assess the relative contributions of farnesylated and/or geranylgeranylated proteins on cell cycle progression from G1 to S phase we designed potent and selective farnesyltransferase (FTI-277) and geranylgeranyltransferase-I (GGTI-298) inhibitors. Flow cytometry studies showed that treatment of NIH3T3 cells with GGTI-298 or lovastatin, which inhibits both protein farnesylation and geranylgeranylation, arrested cells in G0/G1 whereas cells treated with FTI-277 progressed normally through the cell cycle. [3H]thymidine incorporation studies showed that mevalonate and geranylgeraniol, but not farnesol, released the lovastatin G1 block. Furthermore, mevalonate release of the lovastatin G1 block was inhibited by GGTI-298 but not by FTI-277. These results demonstrate that geranylgeranylated proteins are required for cells to proceed from G1 to S phase, and that farnesylated proteins do not play an essential role in the G1 to S phase transition
Vogt
A
A
School of Medicine, Department of Pharmacology, University of Pittsburgh, Pennsylvania 15261, USA.
Qian
Y
Y
McGuire
T F
TF
Hamilton
A D
AD
Sebti
S M
SM
D000199:Actins / Q000187:drug effects / Q000648:ultrastructure; D019883:Alkyl and Aryl Transferases; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004224:Diterpenes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D011905:Genes, ras; D008148:Lovastatin / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000502:physiology; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D014166:Transferases / Q000037:antagonists & inhibitors; D020668:rap GTP-Binding Proteins; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D001549:Benzamides; D004224:Diterpenes; D004791:Enzyme Inhibitors; C096856:FTI 277; C102520:GGTI 297; C102521:GGTI 298; D011518:Proto-Oncogene Proteins; D005204:Farnesol; D004247:DNA; D008148:Lovastatin; D008715:Methionine; C017338:geranylgeraniol; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D018631:ras Proteins; D008798:Mevalonic Acid