Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways.
Cyclin G1 is a p53-responsive gene that is induced in alternative reading frame (ARF)-arrested cells, yet its role in growth control is unclear. We tested its effects on growth and involvement in the ARF-Mdm2-p53 tumor suppressor pathway. We show that cyclin G1 interacts with ARF, Mdm2, and p53 in vitro and in vivo. At high levels, cyclin G1 induces a G(1)-phase arrest in mammalian cells that coincides with p53 activation. Conversely, lower levels of cyclin G1 lack intrinsic growth inhibitory effects yet potentiate ARF-mediated growth arrest. Notably, cyclin G1 is down-regulated by Mdm2 through proteasome-mediated degradation. These data suggest that cyclin G1 is a positive feedback regulator of p53 whose expression is restrained by Mdm2. Interestingly, growth inhibition by cyclin G1 does not require p53 but instead exhibits partial retinoblastoma protein (pRb) dependence. These findings reveal that cyclin G1 has growth inhibitory activity that is mechanistically linked to ARF-p53 and pRb tumor suppressor pathways.
Zhao
Lili
L
Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Samuels
Tina
T
Winckler
Sarah
S
Korgaonkar
Chandrashekhar
C
Tompkins
Van
V
Horne
Mary C
MC
Quelle
Dawn E
DE
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000502:physiology; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins; D012516:Osteosarcoma; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D006131:Growth Inhibitors; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex