Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells.
Cyclin-dependent kinase (Cdk) enzymes are activated for entry into the S phase of the cell cycle. Elimination of Cdk inhibitor protein p27Kip1 during the G1 to S phase is required for the activation process. An inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase prevents its elimination and leads to G1 arrest. Mevalonate and its metabolite, geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate, restore the inhibitory effect of pravastatin on the degradation of p27 and allow Cdk2 activation. By the addition of geranylgeranyl pyrophosphate, Rho small GTPase(s) are geranylgeranylated and translocated to membranes during G1/S progression. The restoring effect of geranylgeranyl pyrophosphate is abolished with botulinum C3 exoenzyme, which specifically inactivates Rho. These results indicate (i) among mevalonate metabolites, geranylgeranyl pyrophosphate is absolutely required for the elimination of p27 followed by Cdk2 activation; (ii) geranylgeranylated Rho small GTPase(s) promote the degradation of p27 during G1/S transition in FRTL-5 cells.
Hirai
A
A
Second Department of Internal Medicine, Chiba University Medical School, Inohana-cho, Chuou-ku, Japan. aizan@med.m.chiba-u.ac.jp
Nakamura
S
S
Noguchi
Y
Y
Yasuda
T
T
Kitagawa
M
M
Tatsuno
I
I
Oeda
T
T
Tahara
K
K
Terano
T
T
Narumiya
S
S
Kohn
L D
LD
Saito
Y
Y
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D007328:Insulin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology; D017368:Protein Prenylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D013972:Thyrotropin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D020741:rho GTP-Binding Proteins
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D007328:Insulin; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013972:Thyrotropin; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D019204:GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D017035:Pravastatin; D008798:Mevalonic Acid