Cyclin G recruits PP2A to dephosphorylate Mdm2.
The function of cyclin G, a commonly induced p53 target, has remained elusive. We show that cyclin G forms a quaternary complex in vivo and in vitro with enzymatically active phosphatase 2A (PP2A) holoenzymes containing B' subunits. Interestingly, cyclin G also binds in vivo and in vitro to Mdm2 and markedly stimulates the ability of PP2A to dephosphorylate Mdm2 at T216. Consistent with these data, cyclin G null cells have both Mdm2 that is hyperphosphorylated at T216 and markedly higher levels of p53 protein when compared to wild-type cells. Cyclin G expression also results in reduced phosphorylation of human Hdm2 at S166. Thus, our data suggest that cyclin G recruits PP2A in order to modulate the phosphorylation of Mdm2 and thereby to regulate both Mdm2 and p53.
Okamoto
Koji
K
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Li
Hongyun
H
Jensen
Michael R
MR
Zhang
Tingting
T
Taya
Yoichi
Y
Thorgeirsson
Snorri S
SS
Prives
Carol
C
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D019556:COS Cells; D002384:Catalysis; D002522:Chlorocebus aethiops; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000737:chemistry / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D009687:Nuclear Proteins; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054648:Protein Phosphatase 2; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011714:Pyrans; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013045:Species Specificity; D013141:Spiro Compounds; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000935:Antifungal Agents; C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D009687:Nuclear Proteins; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D011714:Pyrans; D011993:Recombinant Fusion Proteins; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C053079:tautomycin; D019319:Okadaic Acid; D019000:Phosphotyrosine; D016572:Cyclosporine; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2